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The sponsor decided to terminate the study following an FDA request of a partial clinical hold.
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This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Arm A | Active Comparator | Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if > 75 years of age 20 mg. Cycle 1 will be administered via a Peripheral Venous Catheter (PVC) and cycle 2 and onwards melflufen will be administered via a Central Venous Catheter (CVC). |
|
| Arm B | Active Comparator | Melflufen 40 mg iv Day 1 of each 28 day cycle. Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle, if > 75 years of age 20 mg. Cycle 1 will be administered via a Central Venous Catheter (CVC) and cycle 2 will be administered via a Peripheral Venous Catheter (PVC). From cycle 3 and onwards melflufen will be administered via CVC. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Melphalan | Drug | Peripheral versus central administration |
|
| Measure | Description | Time Frame |
|---|---|---|
| Peak Plasma Concentration for Melphalan | To evaluate and compare the pharmacokinetic (PK) variable Cmax of melphalan after central and peripheral intravenous infusion of melflufen. | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. |
| Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melphalan after central and peripheral intravenous infusion of melflufen. | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. |
| Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melphalan after central and peripheral intravenous infusion of melflufen | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. |
| Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Assessment of the local tolerability of peripheral intravenous administration of melflufen using the Visual Infusion Phlebitis (VIP) scale. The VIP scale provides a score from 0 to 5, noting an ascending order of severity of inflammation. A score of 0 is the lowest possible score, meaning no inflammation detected, and 5 is the highest score, indicating the most severe reaction. | 15 minutes and 4 hours after peripheral intravenous administration, pre- and post-infusion on Day 1 and Day 8 |
| Measure | Description | Time Frame |
|---|---|---|
| Peak Plasma Concentration for Melflufen and Desethyl-melflufen | To evaluate and compare the pharmacokinetic (PK) variable Cmax of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen. | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) |
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Inclusion Criteria:
Male or female, age 18 years or older
Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol;
A prior diagnosis of multiple myeloma (MM) with documented disease progression in need of treatment at time of screening;
Measurable disease defined as any of the following:
Received at least 2 prior lines of therapy and is refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI). The definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles of therapy, see Appendix 10 and Appendix 8.
Adequate peripheral arm veins for repeated intravenous infusions
Life expectancy of ≥ 6 months;
Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, see Appendix 6. Patients with ECOG performance status > 2 solely based on bone pain secondary to MM may be eligible following consultation and approval of medical monitor;
12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec, see Appendix 11;
Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study treatment administration on Cycle 1 Day 1:
Must have or be willing to have an acceptable central catheter (Port a Cath, peripherally inserted central catheter [PICC] line, or central venous catheter [CVC]) and a PVC;
a) Male patients: A male patient is eligible if he agrees to use contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 3 months after the last dose of study treatment and refrains from donating sperm during this period b) Female patients: A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: I. Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 or II. A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and for at least 28 days after the last dose of study treatment
Exclusion Criteria:
Primary refractory disease (i.e. never responded with at least minimal response [MR] to any prior therapy);
Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet count fails to increase by > 10,000 cells/mm³ after a transfusion of an appropriate dose of platelets);
Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant cardiac conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months);
Known active infection that is uncontrolled or has required intravenous systemic therapy within 14 days of randomization. Patients that have required oral anti-infective treatment within 14 days of randomization should be discussed with the Medical Monitor;
Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance;
Pregnant or breast-feeding females;
Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation;
Human immunodeficiency virus (HIV) or active hepatitis B or C viral infection;
Concurrent known or suspected amyloidosis or plasma cell leukemia;
POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);
Known central nervous system (CNS) or meningeal involvement of myeloma
Any of the following treatments, within the specified timeframe
Other washout times may be considered following consultation with the medical monitor.
Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 1 without pain are permitted);
Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy;
Prior allogeneic stem cell transplantation with active graft-versus-host-disease;
Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy);
Known intolerance to the required dose and schedule of steroid therapy, as determined by the investigator;
Known hypersensitivity reaction to melphalan, melflufen or its excipients
Prior treatment with melflufen
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| The Oncology Institute of Hope & Innovation - Glendale | Glendale | California | 91204 | United States | ||
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| ID | Title | Description |
|---|---|---|
| FG000 | Arm A | Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. Melflufen: Peripheral versus central administration Dexamethasone: Oral tablets |
| FG001 | Arm B | Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melflufen: Peripheral versus central administration Dexamethasone: Oral tablets |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Cycle 1 |
|
| ||||||||||||||||||||||||
| Cycle 2 |
| |||||||||||||||||||||||||
| Cycle 3 to End of Study (EOS) |
|
Full Analysis Set
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| ID | Title | Description |
|---|---|---|
| BG000 | Arm A | Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. Melflufen: Peripheral versus central administration Dexamethasone: Oral tablets |
| BG001 |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Peak Plasma Concentration for Melphalan | To evaluate and compare the pharmacokinetic (PK) variable Cmax of melphalan after central and peripheral intravenous infusion of melflufen. | Pharmacokinetic (PK) Set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. |
|
SAEs were collected from signing of the ICF until 30 days after last dose of study treatment or initiation of subsequent therapy, whichever occurred first. Non-serious AEs were collected from the start of study treatment until 30 days after the last dose of any study drug or initiation of subsequent therapy, whichever occurred first. Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer.
Adverse events cannot be compared for Arm A versus Arm B. Because of the crossover design of the study, all patients had a different route of administration in Cycle 2 than Cycle 1, and later AEs could be due to a cumulative effect of multiple treatment cycles. Thus, AEs occurring in Cycle 2 and beyond cannot be attributed to only 1 route of administration.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Arm A | Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. Melflufen: Peripheral versus central administration Dexamethasone: Oral tablets |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA version 24.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA version 24.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| VP Chief Operating Officer | Oncopeptides AB | +46 8 615 20 40 | trials@oncopeptides.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 10, 2021 | May 24, 2022 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 24, 2022 | May 24, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D008558 | Melphalan |
| C585069 | melflufen |
| D003907 | Dexamethasone |
| ID | Term |
|---|---|
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
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| Dexamethasone | Drug | Oral tablets |
|
| Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen |
To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen |
| Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) |
| Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) |
| Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | To evaluate elimination half-life (t½) for melflufen, melphalan and desethyl-melflufen after central and peripheral intravenous infusion of melflufen. | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 measurements during and post infusion (28 days cycle) |
| Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | To assess safety and general tolerability of melflufen by collecting non-serious Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from the time the subject signed the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. | Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer. |
| Best Response (Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD) or Progressive Disease (PD) | To assess best response during the study with the criteria established by the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) for sCR, CR, VGPR, PR, SD and PD | From initiation of therapy until disease progression. Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. |
| ORR | To assess overall response rate (ORR), including CR/sCR, VGPR and PR, during the study with the criteria established by the IMWG-URC. | From initiation of therapy until disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
| CBR | To assess clinical benefit rate (CBR), i.e., proportion of patients that achieve a confirmed minimal response or better (sCR, CR, VGPR, PR and MR), during the study with the criteria established by the IMWG-URC. | To be assessed at the end of study drug treatment. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
| DOR | To assess duration of response (DOR): the time in months from the first evidence of confirmed assessment of sCR, CR, VGPR, or PR to first confirmed disease progression according to the criteria established by the IMWG-URC or to death due to any cause. DOR is defined only for patients with a confirmed PR or better. | From confirmed response until disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
| DOCB | To assess duration of clinical benefit (DOCB) in patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR, or MR during the study with the criteria established by the IMWG-URC. | From first evidence of confirmed assessment of sCR, CR, VGPR, PR or MR to first confirmed disease progression, or to death due to any cause. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
| TTR | To assess time to response (TTR) in patients with PR or better during the study with the criteria established by the UMWG-URC. | From initiation of therapy until documented disease response. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
| TTP | To assess time to progression (TTP) during the study with the criteria established by the IMWG-URC. | From date of randomization until documented disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
| TTNT | To assess time to next treatment (TTNT) | From randomization to the date of next anti-myeloma treatment. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
| PFS | To assess progression free survival (PFS) | From initiation of therapy until documented disease progression or initiation of new therapy. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
| Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | To assess safety and general tolerability of melflufen by collecting non-serious Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from the time the subject signed the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. | Median treatment durations for Arm A and Arm B were 29.14 and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer. |
| Grade 5 Treatment-Emergent Adverse Events (TEAEs) | To assess safety and general tolerability of melflufen by collecting serious adverse events (SAEs) from the signing of the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever comes first. | From signing of the ICF until 30 days after the last dose of any study drug or initiation of subsequent therapy, whichever comes first. Median treatment durations for Arms A and B were 29.14 weeks and 12.14 weeks. AE reporting period=30 days longer |
| Specialized Hospital for Active Treatment of Hematological Diseases, Sofia |
| Sofia |
| Bulgaria |
| Multiprofile Hospital for Active Treatment "Sveta Marina", Varna | Varna | Bulgaria |
| University Hospital Brno, Clinic of Internal Medicine - Hematology and Oncology | Brno | 62500 | Czechia |
| University Hospital Olomouc, Clinic of Hemato-Oncology | Olomouc | 77900 | Czechia |
| Central Hospital of Southern Pest National Institute of Hematology and Infectious Diseases, Department of Hematology and Stem Cell Transplantation | Budapest | Hungary |
| Semmelweis University, 3rd Department of Internal Medicine | Budapest | Hungary |
| Public Non-Profit Enterprise "City Clinical Hospital #4" under Dnipro City Council, Regional Hematology Center | Dnipro | Ukraine |
| Public Non-Profit Enterprise "Kyiv City Clinical Hospital #9" under the Executive Body of Kyiv City Council, Hematology Department #1 | Kyiv | Ukraine |
| Institute of Blood Pathology and Transfusion Medicine, Department of Hematology with Laboratory Group | Lviv | Ukraine |
| COMPLETED |
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| NOT COMPLETED |
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| Discontinued Study in Cycle 3 or Later |
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| COMPLETED |
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| NOT COMPLETED |
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|
| Arm B |
Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melflufen: Peripheral versus central administration Dexamethasone: Oral tablets |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Baseline fertility status | Baseline fertility status for female participants. | Percentages are based on the number of female participants only. | Count of Participants | Participants |
|
Combined treatment ARM for all PVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melflufen: Peripheral versus central administration. Dexamethasone: Oral tablets.
| OG001 | Central Venous Catheter (CVC) | Combined treatment ARM for all CVC administration from both ARM A & ARM B during Cycle 1 and 2. Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). ARM A Cycle 1 administered via a PVC and Cycle 2 and onwards melflufen administered via a CVC. ARM B Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melflufen: Peripheral versus central administration. Dexamethasone: Oral tablets. |
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| Primary | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melphalan | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melphalan after central and peripheral intravenous infusion of melflufen. | Pharmacokinetic (PK) Set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | min*ng/mL | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. |
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| Primary | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melphalan | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melphalan after central and peripheral intravenous infusion of melflufen | Pharmacokinetic (PK) Set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | min*ng/mL | Cycle 1 Day 1 and Cycle 2 Day 1. Samples were collected 5, 10, 15, 20, and 25 minutes after the start of the infusion; immediately before the end of the infusion; and 5, 10, 15, and 30 minutes and 1, 2, and 4 hours after the end of the infusion. |
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| Primary | Number of Participants With Local Reactions Including Phlebitis at Infusion Site After Peripheral Intravenous Administration | Assessment of the local tolerability of peripheral intravenous administration of melflufen using the Visual Infusion Phlebitis (VIP) scale. The VIP scale provides a score from 0 to 5, noting an ascending order of severity of inflammation. A score of 0 is the lowest possible score, meaning no inflammation detected, and 5 is the highest score, indicating the most severe reaction. | Safety Analysis Set | Posted | Count of Participants | Participants | 15 minutes and 4 hours after peripheral intravenous administration, pre- and post-infusion on Day 1 and Day 8 |
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| Secondary | Peak Plasma Concentration for Melflufen and Desethyl-melflufen | To evaluate and compare the pharmacokinetic (PK) variable Cmax of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen. | Pharmacokinetic (PK) Analysis set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) |
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| Secondary | Area Under the Plasma Concentration Versus Time Curve AUC(0-t) of Melflufen and Desethyl-melflufen | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-t) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen | Pharmacokinetic (PK) analysis set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | min x ng/mL | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) |
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| Secondary | Area Under the Plasma Concentration Versus Time Curve AUC(0-inf) of Melflufen and Desethyl-melflufen | To evaluate and compare the pharmacokinetic (PK) variable AUC(0-inf) of melflufen and desethyl-melflufen after central and peripheral intravenous infusion of melflufen | Pharmacokinetic (PK) Analysis set: All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in Cycle 2 were not evaluable for PK. | Posted | Geometric Mean | Geometric Coefficient of Variation | min x ng/mL | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 PK samples during and post infusion (28 days cycle) |
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| Secondary | Elimination Half-life (t1/2) of Melflufen, Melphalan and Desethyl-melflufen | To evaluate elimination half-life (t½) for melflufen, melphalan and desethyl-melflufen after central and peripheral intravenous infusion of melflufen. | Pharmacokinetic (PK) Analysis set:All patients that received at least two melflufen doses of 40 mg and had sufficient PK samples taken at Cycle 1 and 2 for determination of all PK variables. One PK sampling series following peripheral administration and one PK sampling series following central administration. Patients with a dose reduction in cycle 2 were not evaluable for PK. | Posted | Mean | Standard Deviation | minutes | Cycle 1 Day 1 and Cycle 2 Day 1 - 13 measurements during and post infusion (28 days cycle) |
|
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| Secondary | Frequency of Treatment-Emergent Adverse Events (TEAEs) by MedDRA SOC and PT | To assess safety and general tolerability of melflufen by collecting non-serious Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from the time the subject signed the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. | Posted | Count of Participants | Participants | Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer. |
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| Secondary | Best Response (Stringent Complete Response (sCR), Complete Response (CR), Very Good Partial Response (VGPR), Partial Response (PR), Minimal Response (MR), Stable Disease (SD) or Progressive Disease (PD) | To assess best response during the study with the criteria established by the International Myeloma Working Group Uniform Response Criteria (IMWG-URC) for sCR, CR, VGPR, PR, SD and PD | Full Analysis Set: 14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Count of Participants | Participants | From initiation of therapy until disease progression. Median treatment durations for Arm A and Arm B were 29.14 weeks and 12.14 weeks, respectively. |
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| Secondary | ORR | To assess overall response rate (ORR), including CR/sCR, VGPR and PR, during the study with the criteria established by the IMWG-URC. | Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Count of Participants | Participants | From initiation of therapy until disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
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|
|
| Secondary | CBR | To assess clinical benefit rate (CBR), i.e., proportion of patients that achieve a confirmed minimal response or better (sCR, CR, VGPR, PR and MR), during the study with the criteria established by the IMWG-URC. | Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Count of Participants | Participants | To be assessed at the end of study drug treatment. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
|
|
|
| Secondary | DOR | To assess duration of response (DOR): the time in months from the first evidence of confirmed assessment of sCR, CR, VGPR, or PR to first confirmed disease progression according to the criteria established by the IMWG-URC or to death due to any cause. DOR is defined only for patients with a confirmed PR or better. | Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Median | 95% Confidence Interval | months | From confirmed response until disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
|
|
|
| Secondary | DOCB | To assess duration of clinical benefit (DOCB) in patients with stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR, or MR during the study with the criteria established by the IMWG-URC. | Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Median | 95% Confidence Interval | months | From first evidence of confirmed assessment of sCR, CR, VGPR, PR or MR to first confirmed disease progression, or to death due to any cause. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
|
|
|
| Secondary | TTR | To assess time to response (TTR) in patients with PR or better during the study with the criteria established by the UMWG-URC. | Full Analysis set:14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Count of Participants | Participants | From initiation of therapy until documented disease response. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
|
|
|
| Secondary | TTP | To assess time to progression (TTP) during the study with the criteria established by the IMWG-URC. | Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Median | 95% Confidence Interval | months | From date of randomization until documented disease progression. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
|
|
|
| Secondary | TTNT | To assess time to next treatment (TTNT) | Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Median | 95% Confidence Interval | months | From randomization to the date of next anti-myeloma treatment. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
|
|
|
| Secondary | PFS | To assess progression free survival (PFS) | Full Analysis set: 14 participants randomized to Arm A and 13 participants randomized to Arm B. | Posted | Median | 95% Confidence Interval | months | From initiation of therapy until documented disease progression or initiation of new therapy. Maximum treatment durations for Arm A and Arm B were 68.4 and 59.0 weeks, respectively. |
|
|
|
| Secondary | Grade 3/4 Treatment-Emergent Adverse Events (TEAEs) | To assess safety and general tolerability of melflufen by collecting non-serious Adverse Events (AEs) from the start of study treatment until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. Serious AEs (SAEs) were collected from the time the subject signed the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever occurred first. | Posted | Count of Participants | Participants | Median treatment durations for Arm A and Arm B were 29.14 and 12.14 weeks, respectively. The AE reporting period is estimated to be 30 days longer. |
|
|
|
| Secondary | Grade 5 Treatment-Emergent Adverse Events (TEAEs) | To assess safety and general tolerability of melflufen by collecting serious adverse events (SAEs) from the signing of the ICF until 30 days after the last dose of any study drug (melflufen or dexamethasone) or initiation of subsequent therapy whichever comes first. | Posted | Count of Participants | Participants | From signing of the ICF until 30 days after the last dose of any study drug or initiation of subsequent therapy, whichever comes first. Median treatment durations for Arms A and B were 29.14 weeks and 12.14 weeks. AE reporting period=30 days longer |
|
|
|
| 1 |
| 14 |
| 5 |
| 14 |
| 13 |
| 14 |
| EG001 | Arm B | Melflufen 40 mg iv Day 1 of each 28-day cycle. Dexamethasone 40 mg po Days 1,8,15 and 22 of each 28-day cycle (20 mg for patients 75 years or older). Cycle 1 administered via a CVC and Cycle 2 administered via a PVC. From Cycle 3 and onwards melflufen administered via CVC. Melflufen: Peripheral versus central administration Dexamethasone: Oral tablets | 8 | 13 | 9 | 13 | 13 | 13 |
| Ileus | Gastrointestinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Death | General disorders | MedDRA version 24.0 | Systematic Assessment |
|
| General physical health deterioration | General disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Asymptomatic COVID-19 | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| COVID-19 pneumonia | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Femoral neck fracture | Injury, poisoning and procedural complications | MedDRA version 24.0 | Systematic Assessment |
|
| Femur fracture | Injury, poisoning and procedural complications | MedDRA version 24.0 | Systematic Assessment |
|
| Ischaemic stroke | Nervous system disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA version 24.0 | Systematic Assessment |
|
| General physical health deterioration | General disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA version 24.0 | Systematic Assessment |
|
| COVID-19 | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Infection | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Pharyngitis | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Pneumonia | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Respiratory tract infection | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Rhinitis | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA version 24.0 | Systematic Assessment |
|
| Femur fracture | Injury, poisoning and procedural complications | MedDRA version 24.0 | Systematic Assessment |
|
| Body temperature increased | Investigations | MedDRA version 24.0 | Systematic Assessment |
|
| C-reactive protein increased | Investigations | MedDRA version 24.0 | Systematic Assessment |
|
| SARS-CoV-2 test positive | Investigations | MedDRA version 24.0 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Type 2 diabetes mellitus | Metabolism and nutrition disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Aphasia | Nervous system disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Cognitive disorder | Nervous system disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Renal impairment | Renal and urinary disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA version 24.0 | Systematic Assessment |
|
| Rhinorrhoea | Respiratory, thoracic and mediastinal disorders | MedDRA version 24.0 | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA version 24.0 | Systematic Assessment |
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| Hypertension | Vascular disorders | MedDRA version 24.0 | Systematic Assessment |
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| Vascular pain | Vascular disorders | MedDRA version 24.0 | Systematic Assessment |
|
Not provided
Not provided
| D009930 |
| Organic Chemicals |
| D010649 | Phenylalanine |
| D024322 | Amino Acids, Aromatic |
| D000598 | Amino Acids, Cyclic |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D011246 | Pregnadienetriols |
| D011245 | Pregnadienes |
| D011278 | Pregnanes |
| D013256 | Steroids |
| D000072473 | Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D013259 | Steroids, Fluorinated |
| Unknown or Not Reported |
|
| Native Hawaiian or Other Pacific Islander |
|
| Black or African American |
|
| White |
|
| More than one race |
|
| Unknown or Not Reported |
|
| Cycle 2 |
|
|
| Equivalence |
The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25. |
| Cycle 2 |
|
|
| Equivalence |
The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25. |
| VIP score = 2 |
|
| VIP score = 3 |
|
| VIP score = 4 |
|
| VIP score = 5 |
|
| Cycle 1 Day 1 Post-Infusion |
|
|
| Cycle 1 Day 8 |
|
|
| Cycle 2 Day 1 Pre-Infusion |
|
|
| Melflufen Cycle 2 |
|
|
| Desethyl-melflufen Cycle 1 |
|
|
| Desethyl-melflufen Cycle 2 |
|
|
| Equivalence |
The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25. |
| For desmethyl-melflufen: Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients. | [adjusted geometric mean ratio (GMR)] | 0.846 | 2-Sided | 90 | 0.748 | 0.957 | CVC vs PVC CVC is numerator and PVC is denominator. Linear Mixed Effect Model included terms for period, sequence and administration route (PVC or CVC) as fixed effects and subject nested within sequence as a random effect. | Equivalence | The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25. |
| Melflufen Cycle 2 (0-t) |
|
|
| Desethyl-melflufen Cycle 1 (0-t) |
|
|
| Desethyl-melflufen Cycle 2 (0-t) |
|
|
| Equivalence |
The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25. |
| Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients. | adjusted geometric mean ratio (GMR) | 0.897 | 2-Sided | 90 | 0.819 | 0.982 | Data above refer to desethyl-melflufen. CVC vs PVC CVC is numerator, PVC is denominator. Linear Mixed Effect Model included terms for period, sequence and administration route as fixed effects and subject nested within sequence as a random effect. | Equivalence | The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25. |
| Meflufen Cycle 2 (0-inf) |
|
|
| Desethyl-melflufen Cycle 1 (0-inf) |
|
|
| Desethyl-melflufen Cycle 2 (0-inf) |
|
|
| Equivalence |
The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25. |
| Based on a geometric mean ratio (GMR) peripheral vs central of 0.95, a 90% confidence interval (CI) for the ratio of geometric means within bioequivalence limits of 0.8 and 1.25, and 80% power, a sample size of 20 patients (10 per sequence) was required assuming a within-patient variability for period differences (in log scale) of 0.29. Approximately 25 patients were to be enrolled to achieve 20 PK- and local tolerance-evaluable patients. | adjusted geometric mean ratio (GMR) | 0.908 | 2-Sided | 90 | 0.833 | 0.989 | Data above refer to desethyl-melflufen. CVC vs PVC CVC is numerator, PVC is denominator. Linear Mixed Effect Model included terms for period, sequence & administration route as fixed effects and subject nested within sequence as a random effect. | Equivalence | The condition for similarity was if the 90% CI for the GMR was within the bioequivalence limits of 0.8 and 1.25. |
| Melphalan Cycle 2 |
|
|
| Melflufen Cycle 1 |
|
|
| Melflufen Cycle 2 |
|
|
| Desethyl-melflufen Cycle 1 |
|
|
| Desethyl-melflufen Cycle 2 |
|
|
|
| Thrombocytopenia |
|
| Neutropenia |
|
| Anaemia |
|
| Leukopenia |
|
| Infections and Infestations |
|
| Pneumonia |
|
| COVID-19 pneumonia |
|
| Respiratory tract infection |
|
| General disorders and administration site conditions |
|
| Pyrexia |
|
| Fatigue |
|
| General health deterioration |
|
| Musculoskeletal and connective tissue disorders |
|
| Arthralgia |
|
| Back pain |
|
| Bone pain |
|
| Investigations |
|
| SARS-CoV-2 test positive |
|
| C-reactive protein increased |
|
| Injury, poisoning and procedural complications |
|
| femur fracture |
|
| Skin and subcutaneous tissue disorders |
|
| Rash |
|
|
| Very good partial response |
|
| Partial response |
|
| Minimal response |
|
| Stable disease |
|
| Progressive disease |
|
| Not available |
|
|
| Neutropenia |
|
| Anaemia |
|
| Leukopenia |
|
| Lymphopenia |
|
| Febrile neutropenia |
|
| Infections and infestations |
|
| Pneumonia |
|
| COVID-19 pneumonia |
|
| Sepsis |
|
| General disorders and administration site conditions |
|
| General physical health deterioration |
|
| Death |
|
| Asthenia |
|
| Injury, poisoning and procedural complications |
|
| Femur fracture |
|
| Femoral neck fracture |
|
| Gastrointestinal disorders |
|
| Stomatitis |
|
| Musculoskeletal and connective tissue disorders |
|
| Back pain |
|
| Musculoskeletal chest pain |
|
| Nervous system disorders |
|
| Ischaemic stroke |
|
| Vascular disorders |
|
| Hypertension |
|
| Title | Measurements |
|---|---|
|
| COVID-19 pneumonia |
|
| General disorders and administration site conditions |
|
| General physical health deterioration |
|
| Death |
|
| Gastrointestinal disorders |
|
| Ileus |
|