Testing the Effect of Taking Ruxolitinib and CPX-351 in Combination for the Treatment of Advanced Phase Myeloproliferative Neoplasms

A Phase I/II, Open-Label, Multi-Center Study Evaluating the Safety and Efficacy of Ruxolitinib and CPX-351 in Combination for the Treatment of Advanced Phase Myeloproliferative Neoplasms

Sponsors

Lead Sponsor: Uma Borate

Collaborator: Incyte Corporation
Jazz Pharmaceuticals
Oregon Health and Science University

Source OHSU Knight Cancer Institute
Brief Summary

This phase I/II trial studies the best dose of ruxolitinib when given together with CPX-351 and to see how well they work in treating patients with accelerated phase or blast phase myeloproliferative neoplasm. Ruxolitinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. CPX-351 is a mixture of 2 chemotherapy drugs (daunorubicin and cytarabine) given for leukemia in small fat-based particles (liposomes) to improve the drug getting into cancer cells. Giving ruxolitinib and CPX-351 may work better in treating patients with secondary acute myeloid leukemia compared to CPX-351 alone.

Detailed Description

PRIMARY OBJECTIVES: I. To identify the maximum-tolerated dose (MTD) of ruxolitinib in combination with liposome-encapsulated daunorubicin-cytarabine (CPX-351). (Phase I) II. To evaluate the objective response rate in participants with post-myeloproliferative neoplasm (MPN)- accelerated phase (AP)/blast phase (BP) following treatment with the combination of ruxolitinib and CPX-351 (per 2012 MPN-BP criteria). (Phase II) SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of ruxolitinib in combination with CPX-351. (Phase I) II. Assess survival outcomes and proportion of patients receiving transplant associated with ruxolitinib in combination with CPX-351. (Phase II) EXPLORATORY OBJECTIVES: I. To evaluate the rate of response among participants with MPN-AP/BP using European Leukemia Net (ELN) criteria. II. Assess the proportion of treated participants with minimal residual disease. (Phase II) OUTLINE: This is a phase I, dose-escalation study of ruxolitinib followed by a phase II study. INDUCTION: Patients receive CPX-351 intravenously (IV) over 90 minutes on days 1, 3, and 5 and ruxolitinib orally (PO) twice daily (BID) on days 6-28 of cycle 1. RE-INDUCTION: Patients with significant residual disease may receive CPX-351 IV on days 1 and 3 and ruxolitinib PO BID on days 4-28 of cycle 2 per the discretion of the treating physician. Patients who have persistent disease following 2 cycles of therapy (induction and re-induction) will be offered salvage chemotherapy. CONSOLIDATION: Patients that have =< 5% blasts in bone marrow receive CPX-351 IV on days 1 and 3 and ruxolitinib PO BID on days 4-28. Treatment repeats every 28 days for up to 2 cycles provided that counts have partially recovered in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients who successfully complete consolidation therapy with a continued =< 5% blasts in bone marrow and have not undergone an allogeneic stem cell transplantation (SCT) receive ruxolitinib PO BID on days 1-28. Treatment repeats every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. ALLOGENEIC STEM CELL TRANSPLANTATION: Patients may undergo an allogeneic SCT at any time after achieving =< 5% blasts in bone marrow if they have a suitable donor. After completion of study treatment, patients are followed up at 30 days and then every 2 months for up to 1 year.

Overall Status Recruiting
Start Date 2019-02-20
Completion Date 2022-12-31
Primary Completion Date 2021-12-31
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Dose limiting toxicity (DLT) (Phase I) Day 1 to day 42
Proportion of participants that achieve at least an Acute Leukemia Response-Partial response (>= ALR-P, per 2012 myeloproliferative neoplasm - blast phase [MPN-BP] criteria) (Phase 2) Day 1 to end of induction or re-induction cycle (or upon assessment of the bone marrow biopsy performed near the end of these cycles if this occurs later). Cycle length is 28 days.
Secondary Outcome
Measure Time Frame
Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Day 1 to end of 6 cycles with study intervention
Incidence of adverse events as assessed by CTCAE version 5.0 Up to 30 days after last on-study dose
Overall survival (OS) 1 year post treatment
Event-free survival (EFS) Day 1 to treatment failure, progressive disease, relapse, last exam date, or death (whichever is first), up to 2 years
Relapse-free survival (RFS) Date of first documented response (ALR-C) to date of relapse or death from any cause, up to 2 years.
Remission duration Date of first documented response (ALR-C) to date of documented relapse, up to 2 years
Proportion of participants proceeding to transplant Date of enrollment to time of transplant or end of follow-up (if no transplant), up to 2 years
Enrollment 47
Condition
Intervention

Intervention Type: Procedure

Intervention Name: Allogeneic Hematopoietic Stem Cell Transplantation

Description: Undergo allogeneic SCT

Arm Group Label: Treatment (CPX-351, ruxolitinib, allogeneic SCT)

Intervention Type: Drug

Intervention Name: Liposome-encapsulated Daunorubicin-Cytarabine

Description: Given IV

Arm Group Label: Treatment (CPX-351, ruxolitinib, allogeneic SCT)

Intervention Type: Drug

Intervention Name: Ruxolitinib

Description: Given PO

Arm Group Label: Treatment (CPX-351, ruxolitinib, allogeneic SCT)

Eligibility

Criteria:

Inclusion Criteria: - Ability to understand and the willingness to sign a written informed consent document - Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 - Participants eligible for this study have either MPN in accelerated phase (AP) or blast phase (BP), defined as: - MPN-AP is defined by 10% to 19% blasts in the peripheral blood or bone marrow - MPN-BP is defined by >= 20% blasts in the blood or bone marrow - Either MPN-AP or MPN-BP requires a previous diagnosis of polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF) - Participants with ET, PV, or MF that have received prior MPN-associated therapy (e.g., hydroxyurea, hypomethylating agents [azacitidine, decitabine], anti-platelet therapies [e.g., aspirin, anagrelide], as well as JAK2 inhibitor therapy [e.g., ruxolitinib or other investigational JAK2 inhibitor]) are eligible - Female participants of childbearing potential must agree to use adequate contraception (2 forms of contraception or abstinence) from the screening visit until 30 days following the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately - Male participants of childbearing potential having intercourse with females of childbearing potential must agree to abstain from heterosexual intercourse or have their partner use 2 forms of contraception from the screening visit until 90 days until the last dose of study treatment. They must also refrain from sperm donation from the screening visit until 90 days following the last dose of study treatment - Left ventricular ejection fraction at >= 50% as measured by echocardiogram (ECHO) or multigated acquisition (MUGA) scan (14 days prior to initiating study treatment) - Candidate for cytotoxic-intensive induction chemotherapy - Willing to take oral medication - Serum creatinine =< 2 x the upper limit of normal (ULN), or glomerular filtration rate > 20 ml/min/1.73m^2 as calculated by Cockcroft-Gault formula - Serum potassium, magnesium, and calcium (corrected for albumin) within institutional normal limits or can be corrected with supplementation - Total serum bilirubin =< 2.5 x ULN - Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =< 2.5 x ULN Exclusion Criteria: - Ongoing participation in another clinical trial - Isolated myeloid sarcoma (i.e., participants must have blood or marrow involvement with AML to enter the study) - Acute promyelocytic leukemia (French-American-British [FAB] M3 classification) - Active central nervous system (CNS) involvement by AML - Current treatment or treatment within 2 weeks or 5 half-lives (whichever is longer) prior to the first dose of study medication with another investigational medication or current enrollment in another investigational drug protocol (unless there is evidence of rapidly progressive disease in which case a shorter interval from last therapy may be acceptable) - Any unresolved toxicity equal to or greater than grade 2 from previous anticancer therapy, except for stable chronic toxicities not expected to resolve, such as peripheral neurotoxicity - Incomplete recovery from any prior surgical procedures or had surgery within 4 weeks prior to study entry, excluding the placement of vascular access - Disseminated intravascular coagulopathy with active bleeding or signs of thrombosis - Participants with rapidly progressive disease (defined by blast count doubling within 48 hours) or organ dysfunction that would prevent them from receiving these agents - Participants with uncontrolled infection will not be enrolled until infection is treated and symptoms controlled - Participants with an infection receiving treatment (antibiotic, antifungal or antiviral treatment) may be entered into the study but must be afebrile and hemodynamically stable for >= 72 hours (hrs) - Known hypersensitivity to ruxolitinib, cytarabine, daunorubicin, or liposomal products - History of Wilson's disease or other copper metabolism disorder - Uncontrolled intercurrent illness or any concurrent condition that, in the investigator's opinion, would jeopardize the safety of the participant or compliance with the protocol per investigator's discretion. Including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, myocardial infarction within 6 months prior to enrollment, New York Heart Association (NYHA) class III or IV heart failure, severe uncontrolled ventricular arrhythmias - Participants with prior cumulative anthracycline exposure of greater than 368 mg/m^2 daunorubicin (or equivalent) - All participants must discontinue anti-platelet agents or anticoagulants prior to initiation of study drug, including therapeutic doses of aspirin and clopidogrel

Gender:

All

Minimum Age:

18 Years

Maximum Age:

N/A

Healthy Volunteers:

No

Overall Official
Last Name Role Affiliation
Ronan T Swords Principal Investigator OHSU Knight Cancer Institute
Overall Contact

Last Name: Knight Cancer Clinical Trials Hotline

Phone: 503-494-1080

Email: [email protected]

Location
Facility: Status: Contact: Investigator:
OHSU Knight Cancer Institute | Portland, Oregon, 97239, United States Recruiting Ronan T. Swords 503-494-9014 [email protected] Ronan T. Swords Principal Investigator
UT Southwestern/Simmons Cancer Center-Dallas | Dallas, Texas, 75390, United States Recruiting Prapti Patel 214-648-4155 [email protected] Prapti Patel Principal Investigator
Location Countries

United States

Verification Date

2021-05-01

Responsible Party

Type: Sponsor-Investigator

Investigator Affiliation: OHSU Knight Cancer Institute

Investigator Full Name: Uma Borate

Investigator Title: IND Holder

Condition Browse
Number Of Arms 1
Arm Group

Label: Treatment (CPX-351, ruxolitinib, allogeneic SCT)

Type: Experimental

Description: See Detailed Description.

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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