Pacritinib Combined With Decitabine or Cytarabine in Olde... | NCT02532010

NCT02532010

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

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No data is available for this block.

Derived Section

Miscellaneous Info Module

Status Module

Description Module

Detailed Description

This is a single-center, open label, two-arm phase II study of clinical activity of pacritinib in older patients newly diagnosed with AML combined with either decitabine or cytarabine. In this study, approximately 61 patients will be enrolled at the Weill Cornell Medical College. Arm A consists of pacritinib and decitabine and will enroll 31 subjects, and Arm B consists of pacritinib and cytarabine and will enroll 30 subjects. Arm A and B will enroll sequentially. The dose of pacritinib will be 200mg twice a day continuously.

Arm A: Each cycle: Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily.

Arm B: Each cycle: Cytarabine 20mg subcutaneous twice daily for 10 days combined with ongoing pacritinib 200mg twice daily.

Treatment may be given on an outpatient basis if hospitalization is not otherwise required. Every effort should be made to give decitabine or cytarabine consecutively for 10 days; however if interruption is needed, discussion will be held with the medical monitor and the investigator.

The first day of a cycle will be defined as the day on which decitabine or cytarabine is started. First treatment will take place on Cycle 1, day 1. Hydroxyurea may be used at the investigator's discretion for the first 28 days on Cycle 1 to maintain white blood cell count (WBC) <30,000/µl. Bone marrow biopsy and aspiration will be performed between days 22-56 of each cycle and the subsequent treatment cycle will be started between days 22-56, at the investigator's discretion. Ideally, cycles will be administered at 28-day intervals, but treatment delays of decitabine or cytarabine up to 56 days will be permitted to allow resolution of non-hematologic and non-disease-related hematologic toxicities. Granulocyte-stimulating cytokine support will be permitted at the investigator's discretion in the event of neutropenic fever/sepsis as per American Society of Clinical Oncology (ASCO) guidelines.16 Bone marrow aspiration and biopsy will be performed within 5 days of peripheral blood count recovery to an absolute neutrophil count (ANC) ≥ 1000/µL and platelets ≥ 100,000/µL without transfusions, or day 28 whichever comes first. If the peripheral blood absolute blast count is ≥ 5000/µL on day 21 of the first cycle, the second cycle may be administered immediately after bone marrow aspiration and biopsy.

Each arm will enroll in a Simon's two-stage design as described in Section 8. In Arm A, 16 subjects will initially be entered into the study, and if 6 or fewer respond, then Arm A will be terminated early and study will proceed to Arm B. In Arm B, 15 subjects will initially be entered into the study, and if 2 or fewer respond, the study will be terminated early.

Duration of study therapy Patients will receive a minimum of 4 cycles of treatment unless there is evidence of unacceptable regimen-related toxicity or unequivocal disease progression for which the investigator is specifically recommending alternative therapy. Pacritinib will continue throughout the study.

Arm A:

Patients who achieve Complete Remission (CR), Complete Remission with incomplete platelet recovery (CRp), or complete remission with incomplete blood count recovery (CRi) will receive subsequent cycles of decitabine on a monthly basis with decitabine 20mg/m2 IV daily for 5 days with pacritinib. Patients who do not achieve complete remission, but who are responding to treatment (partial response, hematologic response, or clinical benefit as determined by the investigator) will receive four 10-day cycles of decitabine with pacritinib as indicated in the study design, followed by monthly maintenance cycles of decitabine 20mg/m2 IV daily for 5 days + daily pacritinib. The maintenance cycles will continue indefinitely until relapse or toxicity. Patients may be taken off study for allogeneic stem cell transplantation at the discretion of the investigator.

Arm B:

Patients will continue cytarabine 20mg subcutaneous twice daily for 10 days combined with pacritinib for up to 4 cycles to achieve CR, CRp, or CRi. Those patients who achieve CR, CRp, or CRi after 4 cycles may continue to receive monthly maintenance of cytarabine 20mg subcutaneous twice daily for 10 days with pacritinib. The maintenance cycles will continue indefinitely until relapse or toxicity. Patients may be taken off study for allogeneic stem cell transplantation at the discretion of the investigator.

Screening (Study Day -14 to Day 1) Initiate and complete screening activities within 14 days before Cycle 1, Day 1 treatment.

Treatment (Cycle 1, Day 1 through End-of-Treatment Visit) This period begins on the day the patient first receives treatment and ends at the End-of-Treatment Visit.

Follow-up After completion of the End-of-Treatment Visit, all patients are followed up for 30 days and followed every three months for survival and disease status.

Clinical Study Endpoints The Primary objective of the study is to evaluate the safety and efficacy of pacritinib combined with decitabine or cytarabine in newly diagnosed older (≥65 years old) patients with AML. The primary endpoint of this study will be complete remission according to the International Working Group (IWG) criteria.

The following secondary endpoints will be evaluated:

Overall Survival (OS)
Overall remission (OS) rate, defined as CR + CRp + Cri + Partial Remission (PR) based on IWG response criteria
Relapse-free Survival (RFS)
Event-free Survival (EFS)
Time to Complete Response (TTCR)
Remission Duration

DISCUSSION OF STUDY DESIGN

Prognosis for older patients with AML is poor, with median survival of only 9-12 months. Older patients are often not candidates for intensive chemotherapy or allogeneic stem cell transplantation. Decitabine and low-dose cytarabine are frequently used for upfront treatment of older AML patients, however CR rates are 40-50% with decitabine and 18% with cytarabine. Pacritinib is a potent tyrosine kinase inhibitor of FLT3 and Janus Kinase 3 (JAK3) tyrosine kinases. The objective of the proposed clinical trial is to evaluate the efficacy, safety, and feasibility of pacritinib combined with decitabine or cytarabine in newly diagnosed older AML patients. The primary endpoint will be increase in complete remission.

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Arm A: Pacritinib and Decitabine	Active Comparator	Arm A: Each cycle: Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily.	Drug: Pacritinib Drug: Decitabine
Arm B: Pacritinib and Cytarabine	Active Comparator	Arm B: Each cycle: Cytarabine 20mg subcutaneous twice daily for 10 days combined with ongoing pacritinib 200mg twice daily.	Drug: Pacritinib Drug: Cytarabine

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Pacritinib	Drug	Pacritinib is a novel Janus kinase 2-fms-like receptor tyrosine kinase 3 (JAK2-FLT3) inhibitor that has shown promising antitumor activity. Pacritinib is a potent inhibitor of JAK2 and FLT3 kinase activities (50% inhibitory concentration (IC50) = 23 nanomolar (nM)and 22 nM, respectively). The drug also inhibits cellular proliferation in human leukemia and lymphoma cell lines selected for their dependence on either of the target kinases. Consistent with these activities, exposure to pacritinib resulted in the reduction of phos-JAK2, phos-STAT3 or phos-STAT5 in the relevant cell lines. Unlike some JAK2 inhibitors, pacritinib does not inhibit Janus kinase 1 (JAK1).

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Complete Remission Rate	Complete remission rate is defined as number of subjects with complete remission according to the IWG criteria, which is defined by presence of <5 percent of blasts in the bone marrow, absence of blasts with Auer rods, absence of extramedullary disease, absolute neutrophil count >1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); independence of red cell transfusions.	6 months

Secondary Outcomes

Measure	Description	Time Frame
Overall Survival	Survival following treatment to the date of death	2 years
Overall Remission Rate	Overall remission rate is defined as number of subjects with complete remission (CR), Complete Remission with incomplete platelet recovery (CRp), Complete Remission with Incomplete Blood Count Recovery (CRi), Partial Remission (PR) according to the IWG criteria. CRi is defined as All CR criteria except for residual neutropenia (<1.0 x 109/L (1000/µL)) or thrombocytopenia (<100 x 109/L (100,000/µL)), PR is defined as relevant in the setting of phase I and II clinical trials only; all hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25 percent; and decrease of pretreatment bone marrow blast percentage by at least 50 percent.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patient has unequivocal pathologic diagnosis of AML (≥ 20% blasts in the bone marrow based on World Health Organization (WHO) criteria), excluding acute promyelocytic leukemia t(15;17)(q22;q12); Promyelocytic leukemia gene (PML)- retinoic acid receptor alpha (RARA)
Age ≥ 65 years old
No prior treatment for AML except:
- Emergency leukapheresis
- Emergency treatment for hyperleukocytosis with hydroxyurea
- Cranial radiotherapy (RT) for Central Nervous System (CNS) leukostasis (one dose only)
- Growth factor/cytokine support
AML patients with therapy-related myeloid neoplasms are eligible if they have not received radiation therapy or chemotherapy (not including hormonal therapy) for their primary malignancy or disorder for ≥ 6 months. Hydroxyurea may be used at the investigator's discretion up to the first 28 days on Cycle 1 to maintain WBC <30,000/µl.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
Subjects must have adequate hepatic and renal function
Female subject of child-bearing potential and male subjects with female partners of reproductive potential must use acceptable contraceptive methods
Able to understand and to provide written informed consent
Able to comply with all study procedures during the study including all visits and tests
Willing to adhere to the prohibitions and restrictions specified in this protocol
Patient must sign an informed consent form (ICF)

Exclusion Criteria:

Prior treatment with decitabine
Prior treatment with cytarabine
Prior treatment with pacritinib
Presence of serious illness, medical condition, or other medical history, involving the heart, kidney, liver, or other organ system, including abnormal laboratory parameters, which, in the opinion of the Investigator, would be likely to interfere with a subject's participation in the study or with the interpretation of the results.
Active, uncontrolled, clinically significant infection(s)
Have other active malignancies (excluding other myeloid hematologic malignancies) or other malignancies within 12 months before enrollment, except curatively treated non-melanoma skin cancer, cervical intraepithelial neoplasia, organ-confined or treated non-metastatic prostate cancer with negative prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
Are receiving any other investigational therapy or protocol-prohibited therapy
Any prior or co-existing medical condition that in the Investigator's judgment will substantially increase the risk associated with the subject's participation in the study
Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study procedures
Any gastrointestinal (GI) or metabolic condition that could interfere with absorption of oral medication
Inflammatory or chronic functional bowel disorder, such as Crohn's disease, inflammatory bowel disease, chronic diarrhea
Clinically symptomatic and uncontrolled cardiovascular disease
History of any of the following within 6 months: myocardial infarction, severe/unstable angina, or symptomatic congestive heart failure
New York Heart Association Class III or IV congestive heart failure
Patients with National Cancer Institute (NCI) Common Terminology for Adverse Events (CTCAE) grade 2 cardiac arrhythmias may be considered for inclusion with the approval of the investigator if the arrhythmias are stable, asymptomatic and unlikely to affect patient safety. Patients will be excluded if they have ongoing cardiac dysrhythmias of CTCAE grade 3, corrected QT interval (QTc) prolongation >450 ms by Fridericia method, or other factors that increase the risk for QT prolongation (eg, heart failure, hypokalemia [defined as serum potassium < 3.0 milliequivalent (mEq/L) that is persistent and refractory to correction], or family history of long QT interval syndrome).

Name	Affiliation	Role
SangMin Lee, MD	Weill Medical College of Cornell University	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Weill Cornell Medical College		New York	New York	10021	United States

Arm/Group Information

ID	Title	Description
FG000	Arm A: Pacritinib and Decitiabine	Arm A: Each cycle: Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily. Pacritinib: Pacritinib is a novel Janus kinase 2-fms-like receptor tyrosine kinase 3 (JAK2-FLT3) inhibitor that has shown promising antitumor activity. Pacritinib is a potent inhibitor of JAK2 and FLT3 kinase activities (50% inhibitory concentration (IC50) = 23 nM and 22 nM, respectively). The drug also inhibits cellular proliferation in human leukemia and lymphoma cell lines selected for their dependence on either of the target kinases. Consistent with these activities, exposure to pacritinib resulted in the reduction of phos-JAK2, phos-STAT3 or phos-STAT5 in the relevant cell lines. Unlike some JAK2 inhibitors, pacritinib does not inhibit JAK1. Decitabine: Commercial drug: For each cycle Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily.
FG001	Arm B: Pacritinib and Cytarabine	Arm B: Each cycle: Cytarabine 20mg subcutaneous twice daily for 10 days combined with ongoing pacritinib 200mg twice daily. Pacritinib: Pacritinib is a novel Janus kinase 2-fms-like receptor tyrosine kinase 3 (JAK2-FLT3) inhibitor that has shown promising antitumor activity. Pacritinib is a potent inhibitor of JAK2 and FLT3 kinase activities (50% inhibitory concentration (IC50) = 23 nM and 22 nM, respectively). The drug also inhibits cellular proliferation in human leukemia and lymphoma cell lines selected for their dependence on either of the target kinases. Consistent with these activities, exposure to pacritinib resulted in the reduction of phos-JAK2, phos-STAT3 or phos-STAT5 in the relevant cell lines. Unlike some JAK2 inhibitors, pacritinib does not inhibit JAK1. Cytarabine: Commercial drug: For each cycle Cytarabine 20mg subcutaneous twice daily for 10 days combined with ongoing pacritinib 200mg twice daily.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Arm A: Pacritinib and Decitiabine	Arm A: Each cycle: Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily. Pacritinib: Pacritinib is a novel Janus kinase 2-fms-like receptor tyrosine kinase 3 (JAK2-FLT3) inhibitor that has shown promising antitumor activity. Pacritinib is a potent inhibitor of JAK2 and FLT3 kinase activities (50% inhibitory concentration (IC50) = 23 nM and 22 nM, respectively). The drug also inhibits cellular proliferation in human leukemia and lymphoma cell lines selected for their dependence on either of the target kinases. Consistent with these activities, exposure to pacritinib resulted in the reduction of phos-JAK2, phos-STAT3 or phos-STAT5 in the relevant cell lines. Unlike some JAK2 inhibitors, pacritinib does not inhibit JAK1. Decitabine: Commercial drug: For each cycle Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily.

Units	Counts
Participants	BG000

Baseline Measures

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Categorical			Count of Participants

Outcome Measures Module

Outcome Measures

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

Complete Remission Rate

Complete remission rate is defined as number of subjects with complete remission according to the IWG criteria, which is defined by presence of <5 percent of blasts in the bone marrow, absence of blasts with Auer rods, absence of extramedullary disease, absolute neutrophil count >1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); independence of red cell transfusions.

Posted

Count of Participants

Participants

6 months

ID	Title	Description
OG000	Arm A: Pacritinib and Decitiabine	Arm A: Each cycle: Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily. Pacritinib: Pacritinib is a novel Janus kinase 2-fms-like receptor tyrosine kinase 3 (JAK2-FLT3) inhibitor that has shown promising antitumor activity. Pacritinib is a potent inhibitor of JAK2 and FLT3 kinase activities (50% inhibitory concentration (IC50) = 23 nM and 22 nM, respectively). The drug also inhibits cellular proliferation in human leukemia and lymphoma cell lines selected for their dependence on either of the target kinases. Consistent with these activities, exposure to pacritinib resulted in the reduction of phos-JAK2, phos-STAT3 or phos-STAT5 in the relevant cell lines. Unlike some JAK2 inhibitors, pacritinib does not inhibit JAK1. Decitabine: Commercial drug: For each cycle Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily.

Adverse Events Module

Arm/Groups

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: Pacritinib and Decitiabine	Arm A: Each cycle: Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily. Pacritinib: Pacritinib is a novel Janus kinase 2-fms-like receptor tyrosine kinase 3 (JAK2-FLT3) inhibitor that has shown promising antitumor activity. Pacritinib is a potent inhibitor of JAK2 and FLT3 kinase activities (50% inhibitory concentration (IC50) = 23 nM and 22 nM, respectively). The drug also inhibits cellular proliferation in human leukemia and lymphoma cell lines selected for their dependence on either of the target kinases. Consistent with these activities, exposure to pacritinib resulted in the reduction of phos-JAK2, phos-STAT3 or phos-STAT5 in the relevant cell lines. Unlike some JAK2 inhibitors, pacritinib does not inhibit JAK1. Decitabine: Commercial drug: For each cycle Decitabine 20mg/m2 intravenous daily for 10 days combined with ongoing pacritinib 200 mg twice daily.

ID	Term
D007951	Leukemia, Myeloid
D007938	Leukemia
D009370	Neoplasms by Histologic Type
D009369	Neoplasms

ID	Term
D001374	Azacitidine
D001372	Aza Compounds
D009930	Organic Chemicals
D003562	Cytidine

ID	Term
C561234	11-(2-pyrrolidin-1-ylethoxy)-14,19-dioxa-5,7,26-triazatetracyclo(19.3.1.1(2,6).1(8,12))heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene
D000077209	Decitabine
D003561	Cytarabine