Cytarabine and Daunorubicin in Combination With Ruxolitinib for the Treatment of Secondary Acute Myeloid Leukemia Transformed From Myeloproliferative Neoplasms.

• ClinicalTrials.gov Identifier: NCT03878199
• Recruitment Status: Recruiting
• First Posted: March 18, 2019
• Last Update Posted: March 18, 2019
• Sponsor: OHSU Knight Cancer Institute
• Collaborators: Incyte Corporation; Jazz Pharmaceuticals; National Cancer Institute (NCI)
• Information provided by (Responsible Party): Uma Borate, OHSU Knight Cancer Institute

Study Description

Brief Summary:

This phase I/II studies the safety and efficacy of ruxolitinib in combination with liposomal formulation of cytarabine and daunorubicin (CPX-351) for treatment of secondary acute myelogenous leukemia (AML) transformed from myeloproliferative neoplasms (MPNs). The phase I portion of the study will establish the maximum tolerated dose (MTD) for ruxolitinib in combination with a fixed dose of CPX-351. The modified Toxicity Probability Interval (mTPI) design will be used to determine the optimal dose of ruxolitinib in combination with CPX-351. Once the MTD is established and phase I objectives completed, the study will open for enrollment in the phase II portion of the trial. The phase II portion of the trial will assess the efficacy of the ruxolitinib and CPX-351 combination. Prior publications highlight the important role of the janus kinase inhibitor, ruxolitinib in the treatment of MPNs and its preliminary efficacy in combination with hypomethylating agents for the treatment of secondary AML.

Condition or disease	Intervention/treatment	Phase
Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia	Drug: Ruxolitinib; Drug: CPX-351	Phase 1; Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. Phase I: To evaluate the MTD of ruxolitinib in combination with CPX-351 for treatment of post-MPN AML.

II. Phase II. To evaluate the rate of composite complete remission in patients with secondary AML transformed from MPNs (PV, ET and MF) following treatment with the combination of Ruxolitinib and CPX-351 (8 weeks at end of induction or re-induction). The composite complete remission (CRc) includes complete remission (morphologic CR) and complete remission with incomplete count recovery (CRi).

SECONDARY OBJECTIVES:

I. Phase I: To evaluate the safety and tolerability of ruxolitinib in combination with CPX-351 for treatment of post-MPN AML II. Phase II: Assess survival outcomes and proportion of patients receiving transplant associated with ruxolitinib in combination with CPX-351.

III. Phase II: Assess safety and incidence of adverse events as assessed by CTCAE v5.0.

EXPLORATORY OBJECTIVES:

I. Phase II: Assess the proportion of treated (completion of induction or re-induction) participants with sub-clinical levels of AML (i.e., minimal residual disease, MRD) as measured by flow cytometry and/or next generation sequencing of known mutations (e.g., JAK-2, CALR and other disease-specific mutations) at the end of 6 months. Cytogenetic and molecular remission will be measured.

OUTLINE:

Phase I. Eligible participants will first receive induction therapy consisting of intravenous CPX-351 (65 u/m2) administered on day 1, 3, and 5, which will be followed by a 23 day course of ruxolitinib (days 6 to 28) that will be given at a starting dose of 20 mg BID and will increase according to the mTPI dose escalation/de-escalation rule (up to the maximum dose of 25 mg BID). A bone marrow aspirate/biopsy will be performed between D14-D22 to assess disease status and possible need for re-induction. A recovery bone marrow aspirate/biopsy to assess response to induction will be performed between D35-D42 or when ANC>500 and platelet count > 50,000 per microliter; depend on which events occurs first. An enrollment of up to 24 participants is planned for the phase I portion of this study.

Phase II. Once the MTD is established and phase I objectives completed, the study will open for enrollment in the phase II portion of the trial. The phase II portion of the trial will assess the efficacy of the ruxolitinib and CPX-351 combination by evaluating the rate of composite complete remission in participants using a Simon's two-stage minimax design. Enrollment in phase II is planned for a total of 26 participants. The combination treatment regimen will be the same as described for phase I except that ruxolitinib dose will also be fixed per the recommended phase 2 dose (RP2D)(i.e., established MTD).

Participants are eligible to proceed to allogeneic hematopoietic stem cell transplantation (allo-HSCT) at any time after achieving complete remission (CR/CRi) if they have a suitable donor. In this case, participants will come off treatment and be followed for disease status and survival outcomes, including peri-transplant data

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 47 participants
• 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 Secondary Acute Myeloid Leukemia Transformed From Myeloproliferative Neoplasms.
• Actual Study Start Date: February 20, 2019
• Estimated Primary Completion Date: December 31, 2021
• Estimated Study Completion Date: December 31, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: Ruxolitinib in combination with CPX-351; Phase I, participants start with induction therapy consisting of intravenous CPX-351 (65 u/m2) administered on day 1, 3, and 5, which will be followed by a 23 day course of ruxolitinib (days 6 to 28) that will be given at a starting dose of 20 mg BID and will increase according dose escalation/de-escalation rule. A bone marrow aspirate/biopsy will be performed between day 14-22 and potentially again on day 35-42 to assess disease status and possible need for re-induction. Those with CR/CRi after induction will receive 1-2 cycles of consolidation therapy. Participants who completed consolidation therapy with CR/CRi and have not undergone allo-HSCT will complete 12 months of maintenance therapy with ruxolitinib according to established dose derived during phase I. For Phase II, drug regimen, schedule and assessments will remain the same as phase I except that ruxolitinib will be administered at the MTD or recommended phase II dose (RP2D).

Drug: Ruxolitinib; PO, B.I.D.; Other Names: INCB-18424 Phosphate; Jakafi; Drug: CPX-351; Given IV; Other Names: Cytarabine; Daunorubicin

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) of ruxolitinib given in combination with CPX-351. [ Time Frame: Day 1 to end of first induction (Day 28) ]
   DLT of ruxolitinib given in combination with CPX-351. DLT is defined as treatment related ≥ Grade 3 non-hematological or ≥ Grade 4 hematological toxicity.
2. Rate of composite complete remission (CRc), morphologic CR, and CRi [ Time Frame: Day 1 to 8 weeks post induction or re-induction ]
   A Simon's two-stage minimax design will be used. The null hypothesis that the true composite complete remission rate is 0.35 (based on historical data) will be tested against a one-sided alternative of a composite complete remission rate of 0.60 with the combination of CPX-351 and ruxolitinib. In the first stage, 18 patients will be accrued. If there are 6 or fewer composite complete remissions in these 18 patients by the end of induction or re-induction therapy, the study will be stopped. Otherwise, 8 additional patients will be accrued for a total of 26 patients. The null hypothesis will be rejected and the combination therapy deemed promising if 14 or more composite complete remissions are observed during induction or consolidation cycles among the 26 patients.

Secondary Outcome Measures :

1. Incidence of adverse events as assessed by CTCAE version 4.03 [ 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 v4.03.
2. Progression Free Survival (PFS) [ Time Frame: 1 year post treatment ]
   Time-to-event analysis (e.g., Kaplan-Meier and cumulative incidence curves) will be used to evaluate event-free and overall survival. A point estimate and confidence interval will be computed for the proportion of participants who undergo an allo-SCT.
3. Overall Survival (OS) [ Time Frame: 1 year post treatment ]
   Time-to-event analysis (e.g., Kaplan-Meier and cumulative incidence curves) will be used to evaluate overall survival.
4. Proportion of patients 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 allo-SCT (stem cell transplant).

Other Outcome Measures:

1. Proportion of participants with minimal residual disease (MRD) at end of induction. [ 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).
2. Proportion of participants with minimal residual disease (MRD) at end of re-induction. [ 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).
3. Proportion of participants with minimal residual disease (MRD) at end of maintenance. [ 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).
4. Frequency of each mutation (single nucleotide polymorphism (SNP)) [ Time Frame: End of induction or re-induction, up to 6 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:

1. Ability to understand and the willingness to sign a written informed consent document.
2. Age ≥18 years at time of informed consent. Both men and women and members of all races and ethnic groups will be included.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2

4. Newly diagnosed secondary AML patients (including transformed AML).

   1. Diagnosis of essential thrombocythemia, polycythemia vera, or myelofibrosis (based on prior bone marrow biopsy or presence of known MPN-associated mutations [e.g., JAK2, CALR and MPL]) that has transformed to AML after receiving one/multiple of the treatments listed below :Hydroxyurea, HMA therapy,
   2. JAK2 inhibitors including ruxolitinib , and/or
   3. Anti-platelet therapies, including hydroxyurea and anagrelide are allowable.
5. Female patients 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.
6. Male patients 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.
7. Left ventricular ejection fraction at >/= 50% above the lower limit of institutional normal by echocardiogram (ECHO) or multigated acquisition (MUGA) scan (14 days prior).
8. Candidate for cytotoxic-intensive induction chemotherapy.
9. Must be able to take oral medication.

10. Adequate organ function as defined by the following:

    1. Serum creatinine ≤2× the upper limit of normal (ULN), or glomerular filtration rate >20ml/h as calculated by Cockgroft-Gault formula.
    2. Serum potassium, magnesium, and calcium (corrected for albumin) within institutional normal limits or can be corrected with supplementation.
    3. Total serum bilirubin ≤2.5× ULN.
    4. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) ≤2.5× ULN.

Exclusion Criteria:

1. Ongoing participation in another clinical trial.
2. Isolated myeloid sarcoma (i.e., participants must have blood or marrow involvement with AML to enter the study).
3. Acute promyelocytic leukemia (FAB M3 Classification)
4. Active central nervous system (CNS) involvement by AML.
5. 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.
6. 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.
7. Participants with rapidly progressive disease or organ dysfunction that would prevent them from receiving these agents.

8. Participants with uncontrolled infection will not be enrolled until infection is treated and symptoms controlled.

   a. 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 hrs.

9. Known hypersensitivity to ruxolitinib, cytarabine, daunorubicin, or liposomal products.
10. History of Wilson's disease or other copper metabolism disorder.
11. Uncontrolled intercurrent illness or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the patient 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.
12. Patients with prior cumulative anthracycline exposure of greater than 368 mg/m2 daunorubicin (or equivalent).
13. All patients must discontinue anti-platelet agents or anticoagulants prior to initiation of study drug, including aspirin and clopidogrel.

Contacts and Locations

Contacts

Contact: Tara Macey; 503-494-3835; maceyt@ohsu.edu

Locations

United States, Oregon

OHSU Knight Cancer Institute; Recruiting

Portland, Oregon, United States, 97239

Contact: Tara Macey, PhD 503-494-3835 maceyt@ohsu.edu

Principal Investigator: Uma Borate, MD

Sponsors and Collaborators

OHSU Knight Cancer Institute

Incyte Corporation

Jazz Pharmaceuticals

National Cancer Institute (NCI)

Investigators

• Principal Investigator: Uma Borate, MD; OHSU Knight Cancer Institute

More Information

• Responsible Party: Uma Borate, Principal Investigator, OHSU Knight Cancer Institute
• ClinicalTrials.gov Identifier: NCT03878199 History of Changes
• Other Study ID Numbers: STUDY00018059
• First Posted: March 18, 2019
• Last Update Posted: March 18, 2019
• Last Verified: March 2019

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

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Myeloproliferative Disorders; Neoplasms; Neoplasms by Histologic Type; Leukemia, Lymphoid; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Bone Marrow Diseases; Hematologic Diseases; Cytarabine; Daunorubicin; 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