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

• ClinicalTrials.gov Identifier: NCT03878199
• Recruitment Status: Recruiting
• First Posted: March 18, 2019
• Last Update Posted: May 24, 2022
• Sponsor: Ohio State University Comprehensive Cancer Center
• Collaborators: Incyte Corporation; Jazz Pharmaceuticals
• Information provided by (Responsible Party): Uma Borate, Ohio State University Comprehensive Cancer Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Essential Thrombocythemia; Myelofibrosis; Myeloproliferative Neoplasm; Polycythemia Vera; Secondary Acute Myeloid Leukemia	Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Drug: Ruxolitinib	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 47 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: February 20, 2019
• Estimated Primary Completion Date: December 31, 2023
• Estimated Study Completion Date: December 31, 2024

Arms and Interventions

Arm

Intervention/treatment

Experimental: Treatment (CPX-351, ruxolitinib, allogeneic SCT); See Detailed Description.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Undergo allogeneic SCT; Other Names: Allogeneic; Allogeneic Hematopoietic Cell Transplantation; Allogeneic Stem Cell Transplantation; HSC; HSCT; Stem Cell Transplantation, Allogeneic; Drug: Liposome-encapsulated Daunorubicin-Cytarabine; Given IV; Other Names: CPX-351; Cytarabine-Daunorubicin Liposome for Injection; Daunorubicin and Cytarabine (Liposomal); Liposomal AraC-Daunorubicin CPX-351; Liposomal Cytarabine-Daunorubicin; Liposome-encapsulated Combination of Daunorubicin and Cytarabine; Vyxeos; Drug: Ruxolitinib; Given PO; Other Names: INCB-18424; INCB18424; Jakafi; Oral JAK Inhibitor INCB18424

Outcome Measures

Primary Outcome Measures :

1. Dose limiting toxicity (DLT) (Phase I) [ Time Frame: Day 1 to day 42 ]
   DLT occurrence after exposure to ruxolitinib and CPX-351.
2. 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) [ Time Frame: 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. ]
   Will compute the proportion of efficacy-evaluable participants achieving overall response rate (ORR) and the exact binominal 95% confidence interval.

Secondary Outcome Measures :

1. Incidence of adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [ Time Frame: Day 1 to end of 6 cycles with study intervention ]
   The incidence of treatment-related toxicity and the exact confidence interval will be measured. Each toxicity event will be tabulated and summarized by severity and major organ site according to the CTCAE version (v)5.0.
2. Incidence of adverse events as assessed by CTCAE version 5.0 [ Time Frame: Up to 30 days after last on-study dose ]
   The incidence of treatment-related toxicity and the exact confidence interval will be measured. Each toxicity event will be tabulated and summarized by severity and major organ site according to the CTCAE v5.0.
3. Overall survival (OS) [ Time Frame: 1 year post treatment ]
   Time-to-event analysis (e.g., Kaplan-Meier curves or cumulative incidence curves) will be used to evaluate overall survival.
4. Event-free survival (EFS) [ Time Frame: Day 1 to treatment failure, progressive disease, relapse, last exam date, or death (whichever is first), up to 2 years ]
   Time-to-event analysis (e.g., Kaplan-Meier curves or cumulative incidence curves) will be used to evaluate event-free survival.
5. Relapse-free survival (RFS) [ Time Frame: Date of first documented response (ALR-C) to date of relapse or death from any cause, up to 2 years. ]
   Time-to-event analysis (e.g., Kaplan-Meier curves or cumulative incidence curves) will be used to evaluate relapse-free survival.
6. Remission duration [ Time Frame: Date of first documented response (ALR-C) to date of documented relapse, up to 2 years ]
   Time-to-event analysis (e.g., Kaplan-Meier curves or cumulative incidence curves) will be used to evaluate remission duration.
7. Proportion of participants proceeding to transplant [ Time Frame: Date of enrollment to time of transplant or end of follow-up (if no transplant), up to 2 years ]
   A point estimate and 95% confidence interval will be computed for the proportion of participants who undergo an allogeneic (allo)-SCT (stem cell transplant).

Other Outcome Measures:

1. Proportion of participants that achieve at least a complete remission with incomplete marrow recovery (CRi) (per European Leukemia Net [ELN] criteria) [ Time Frame: Day 1 to end of induction or re-induction cycle (up to 8 weeks after start of study treatment) ]
2. Rate of CCR; which is the proportion of participants that achieve at least a MLFS (per ELN criteria) [ Time Frame: Day 1 to end of induction or re-induction cycle (up to 8 weeks after start of study treatment) ]
3. Proportion of participants who have an minimal residual disease (MRD) negative status [ Time Frame: End of induction, up to 2 months on study ]
   Detection of MRD will be achieved by either multi-color flow cytometry (MFC) or next-generation sequencing (NGS) technology and examined using regression based analysis (e.g., logistic regression and Cox regression).
4. Proportion of participants who have an MRD negative status [ Time Frame: End of re-induction, up to 4 months on study ]
   Detection of MRD will be achieved by either multi-color flow cytometry (MFC) or next-generation sequencing (NGS) technology and examined using regression based analysis (e.g., logistic regression and Cox regression).
5. Proportion of participants who have an MRD negative status [ Time Frame: Up to 12 months on study ]
   Detection of MRD will be achieved by either multi-color flow cytometry (MFC) or next-generation sequencing (NGS) technology and examined using regression based analysis (e.g., logistic regression and Cox regression).
6. Frequency of each mutation (single nucleotide polymorphism [SNP]) [ Time Frame: End of induction or re-induction, up to 2 months on study ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Contacts

Contact: The Ohio State University Comprehensive Cancer Center; 800-293-5066; OSUCCCClinicaltrials@osumc.edu

Locations

United States, Ohio

Ohio State University Comprehensive Cancer Center; Recruiting

Columbus, Ohio, United States, 43210

Contact: Molly Brandenburg 614-685-9573 molly.brandenburg@osumc.edu

Principal Investigator: Uma Borate, MD

Sponsors and Collaborators

Ohio State University Comprehensive Cancer Center

Incyte Corporation

Jazz Pharmaceuticals

Investigators

• Principal Investigator: Uma Borate, MD; The Ohio State Comprehensive Cancer Center

More Information

Additional Information:

The Jamesline 

• Responsible Party: Uma Borate, Principal Investigator, Ohio State University Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT03878199
• Other Study ID Numbers: OSU-20393; NCI-2019-03712 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
• First Posted: March 18, 2019
• Last Update Posted: May 24, 2022
• Last Verified: May 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms; Polycythemia Vera; Myeloproliferative Disorders; Polycythemia; Thrombocytosis; Thrombocythemia, Essential; Bone Marrow Diseases; Hematologic Diseases; Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Blood Platelet Disorders; Blood Coagulation Disorders; Hemorrhagic Disorders; Cytarabine; Daunorubicin; Janus Kinase Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors