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Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors
Prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors.
The study will include a pre-treatment (screening) phase (within 14 days before the first lurbinectedin or itraconazole administration) followed by a treatment phase consisting of two lurbinectedin cycles, one cycle in combination with itraconazole and one cycle as single agent (in different order depending on the study sequence), and one additional third cycle of lurbinectedin as a single agent for patients who meet the continuation criteria and obtain a clinical benefit after the first two cycles, and then follow-up of adverse events if any.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sequence TR | Active Comparator | Sequence 1 (TR)
PART A The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m². In Part A, all patients will receive itraconazole plus lurbinectedin in Cycle 1 and lurbinectedin alone in Cycles 2 and 3 (this last cycle being optional). PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences. |
|
| Sequence RT | Active Comparator | Sequence 2 (RT):
|
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Lurbinectedin alone | Drug | The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetic Analysis: Dose-adjusted AUC(0-∞) | The primary parameter of interest for the statistical analysis will be plasma dose adjusted AUC(0-∞) | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetic Analysis: Dose-normalized AUC(0-t) | The dose-normalized area under the concentration-time curve (AUC) will be calculated using the linear-log trapezoidal rule with extrapolation to infinity. | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
| Pharmacokinetic Analysis: Dose-normalized Cmax |
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Inclusion Criteria:
Exclusion Criteria:
Concomitant diseases/conditions:
Symptomatic, progressive or corticosteroids-requiring documented brain metastases or leptomeningeal disease involvement. Patients with asymptomatic documented stable brain metastases not requiring corticosteroids during the last four weeks are allowed.
Use of (strong or moderate) inhibitors or inducers of CYP3A4 activity within three weeks prior to Day 1 of Cycle 1.
Use of CYP3A4 substrates such as HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and simvastatin for which concomitant administration with strong CYP3A4 inhibitor is contraindicated (App 3).
Treatment with any investigational product within the 30 days before Day 1 of Cycle 1.
Women who are pregnant or breast feeding and fertile patients (men and women) who are not using an effective method of contraception (see App 2).
Psychiatric illness/social situations that would limit compliance with study requirements.
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| Name | Affiliation | Role |
|---|---|---|
| Sara MartÃnez Gonzalez, MD | PharmaMar | Study Director |
| Rubin Lubomirov, MD, PhD | PharmaMar | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Fundacion Jimenez Diaz | Madrid | 28040 | Spain | |||
| Hospital HM Sanchinarro |
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14 patients were included and treated at 2 sites: 3 in Part A in Sequence 1 (S1 TR: ITZ+lurbinectedin in Cycle 1) and 11 in Part B, of them 5 in S1 and 6 in Sequence 2 (S2 RT: ITZ+lurbinectedin in Cycle 2). In Part A, all patients were assigned to S1 TR, while in Part B, patients were randomly assigned at a 1:1 ratio to S1 TR or S2 RT.
Patients participated between 7Oct2020 and 3Mar2022 (last follow-up). The 1st dose of the 1st cycle on 15Oct2020. The last dose of the last cycle on 7Feb2022.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part A - S1 (TR) | PART A The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m². In Part A, all patients will receive itraconazole plus lurbinectedin in Cycle 1 and lurbinectedin alone in Cycles 2 and 3 (this last cycle being optional). Sequence 1 (TR)
Lurbinectedin alone: The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole. Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A |
| FG001 | Part B - S1 (TR) | PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences. Sequence 1 (TR)
Lurbinectedin alone: The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole. Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A |
| FG002 | Part B - S2 (RT) | PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences. Sequence 2 (RT):
Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Part A - S1 (TR) | PART A The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m². In Part A, all patients will receive itraconazole plus lurbinectedin in Cycle 1 and lurbinectedin alone in Cycles 2 and 3 (this last cycle being optional). Sequence 1 (TR)
Lurbinectedin alone: The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole. Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | 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 | Pharmacokinetic Analysis: Dose-adjusted AUC(0-∞) | The primary parameter of interest for the statistical analysis will be plasma dose adjusted AUC(0-∞) | The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction. Part A was meant to ensure the adequacy of the dose of lurbinectedin (0.8 mg/m²) when given in combination with itraconazole, and patients (n=3) were not randomized for treatment sequence, so they were not included in the main analysis, as pre-specified in protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | μg·h/L/mg | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
|
Three 21-days cycles
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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 | ITZ+LRB Cycle | The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A was 0.8 mg/m², and in Part B was susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. Patients treated in Part A were not evaluable for PK but were evaluable for safety. For that reason, this arm is reported in the safety section but not in the PK section. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Alanine aminotransferase increased | Investigations | MedDRA (23.0) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Neutropenia | Blood and lymphatic system disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Developtment, Department of PharmaMar's Oncology, Business Unit | Pharma Mar S.A. | 0034918466000 | clinicaltrials@pharmamar.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 18, 2021 | Feb 20, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 27, 2022 | Dec 2, 2022 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C568606 | PM 01183 |
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This is a prospective, open-label, two-way crossover, phase Ib drug-drug interaction study in patients with advanced solid tumors.
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| Lurbinectedin+Itraconazole co-administration | Drug | The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. |
|
The maximum dose-normalized plasma concentration (Cmax) will be obtained directly from the experimental data. |
| Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
| Pharmacokinetic Analysis: T1/2 | Terminal half-life (T1/2) will be obtained from the terminal rate constant calculated by linear regression using at least 3 observations. | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
| Pharmacokinetic Analysis: Total Body Clearance (CL) | Total body clearance (CL), calculated by dividing the administered dose by the AUC with extrapolation to infinity. | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
| Pharmacokinetic Analysis: Volume of Distribution | Volume of distribution (both at steady state and based on the terminal phase) (Vss and Vz, respectively): Vss is an estimate that equals mean residence time times total body clearance. Vz, calculated dividing the administered dose by the product of the AUC with extrapolation to infinity by the terminal rate constant | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
| Madrid |
| 28050 |
| Spain |
| Adverse Event |
|
| Withdrawal by Subject |
|
| BG001 | Part B - S1 (TR) | PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences. Sequence 1 (TR)
Lurbinectedin alone: The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole. Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A |
| BG002 | Part B - S2 (RT) | PART B Randomization will apply for study Part B only. In Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. In Part B, patients will be randomly assigned to the corresponding sequences. Sequence 2 (RT):
Lurbinectedin+Itraconazole co-administration: The dose of lurbinectedin when given in combination with itraconazole for the initial three patients in Part A will be 0.8 mg/m², and in Part B is susceptible to be adjusted properly if deemed necessary based on exposure and safety experience in Part A. |
| BG003 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| ECOG PS | Eastern Cooperative Oncology Group (ECOG) performance status (PS) The ECOG PS scale indicates increasing levels of disability, with 0 indicating fully active; 1, restricted in strenuous activity; 2, restricted in work activity but ambulatory and capable of self-care; 3, capable of limited self-care; 4, completely disabled; and 5, dead | Count of Participants | Participants |
|
| Weight | Median | Full Range | kg |
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| Height | Median | Full Range | cm |
|
| Stage at diagnosis | Stage measures how far a cancer has spread from its origin. The staging system used by CDC's National Program of Cancer Registries and the National Cancer Institute's Surveillance, Epidemiology, and End Results program is called Summary Stage. | Count of Participants | Participants |
|
| Primary tumor | Count of Participants | Participants |
|
| Number of sites at baseline | Median | Full Range | sites |
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| Sites at baseline | Count of Participants | Participants |
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| Time from diagnosis to first infusion | Median | Full Range | years |
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| Prior surgery | Prior surgery yes | Count of Participants | Participants |
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| Prior radiotherapy | Prior radiotherapy yes | Count of Participants | Participants |
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| Number of prior lines | Median | Full Range | lines |
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| Prior lines | Count of Participants | Participants |
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| Number of prior chemotherapy lines | Median | Full Range | Lines of chemotherapy |
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| Prior chemotherapy lines | Count of Participants | Participants |
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| OG001 | LRB Alone | The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the lurbinectedin alone. |
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| Secondary | Pharmacokinetic Analysis: Dose-normalized AUC(0-t) | The dose-normalized area under the concentration-time curve (AUC) will be calculated using the linear-log trapezoidal rule with extrapolation to infinity. | The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction | Posted | Geometric Mean | Geometric Coefficient of Variation | μg·h/L/mg | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
|
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| Secondary | Pharmacokinetic Analysis: Dose-normalized Cmax | The maximum dose-normalized plasma concentration (Cmax) will be obtained directly from the experimental data. | The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction | Posted | Geometric Mean | Geometric Coefficient of Variation | μg/L/mg | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
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| Secondary | Pharmacokinetic Analysis: T1/2 | Terminal half-life (T1/2) will be obtained from the terminal rate constant calculated by linear regression using at least 3 observations. | The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
|
|
|
|
| Secondary | Pharmacokinetic Analysis: Total Body Clearance (CL) | Total body clearance (CL), calculated by dividing the administered dose by the AUC with extrapolation to infinity. | The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
|
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| Secondary | Pharmacokinetic Analysis: Volume of Distribution | Volume of distribution (both at steady state and based on the terminal phase) (Vss and Vz, respectively): Vss is an estimate that equals mean residence time times total body clearance. Vz, calculated dividing the administered dose by the product of the AUC with extrapolation to infinity by the terminal rate constant | The pharmacokinetic analysis included data from only PK - evaluable patients from study Part B and the same study population was used to perform the statistical analysis in evaluating the ITZ - lurbinectedin drug-drug interaction | Posted | Geometric Mean | Geometric Coefficient of Variation | L | Day 1, 2, 3, 5, 8, 11, 15, 22 (Cycle 1,2,3) (each cycle is 21 days) |
|
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|
|
| 1 |
| 13 |
| 4 |
| 13 |
| 12 |
| 13 |
| EG001 | LRB Alone Cycle | The dose of lurbinectedin during Parts A and B will be 3.2 mg/m² for all patients when administered without itraconazole. | 1 | 14 | 5 | 14 | 13 | 14 |
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Small intestinal obstruction | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Rhabdomyolysis | Musculoskeletal and connective tissue disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Intestinal obstruction | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Deep vein thrombosis | Vascular disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Vomiting | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Fatigue | General disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Bone pain | Musculoskeletal and connective tissue disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Dysgeusia | Nervous system disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Syncope | Nervous system disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Abdominal pain | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Intestinal pseudo-obstruction | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Stomatitis | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Stoma site infection | Infections and infestations | MedDRA (23.0) | Non-systematic Assessment |
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| Decreased appetite | Metabolism and nutrition disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Back pain | Musculoskeletal and connective tissue disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Acute kidney injury | Renal and urinary disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Diarrhoea | Gastrointestinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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| Tumour pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA (23.0) | Non-systematic Assessment |
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| Respiratory failure | Respiratory, thoracic and mediastinal disorders | MedDRA (23.0) | Non-systematic Assessment |
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The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days from the time submitted to the sponsor for review.