Phase I/II Trial of CPX-351 + Palbociclib in Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and tolerability of Palbociclib in combination with investigational (experimental) drug, CPX-351 and evaluate the efficacy of Palbociclib in combination with chemotherapy as measured by overall response rate (ORR), i.e. complete response (CR) and CR with incomplete blood count recovery (CRi) by 2003 IWG criteria.

Detailed Description
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The objectives of this study are to evaluate the safety and tolerability of Palbociclibin combination with CPX-351, and to evaluate the efficacy of Palbociclibin combination with chemotherapy as measured by overall response rate (ORR), i.e. complete response (CR) and CR with incomplete blood count recovery (CRi) by IWG criteria. CPX-351 is an investigational drug that works as formulation of a fixed combination of the antineoplastic (acting to prevent, inhibit or halt the development of a neoplasm (a tumor)) drugs cytarabine and daunorubicin. Palbociclibis an investigational drug that works to induce early G1 arrest by inhibiting CDK4/6, which are two types of CDKs that are overexpressed in AML cell cancer lines. CPX-351 and Palbociclib is experimental because it is not approved by the Food and Drug Administration (FDA). This is a single arm, open label study of the combination of Palbociclib with CPX-351 in adults with AML. The trial consists of two components: phase I to evaluate the safety with dose escalation of Palbociclib in combination with CPX-351 and phase II to evaluate the overall response rate of the combination in the targeted participant population.

Official Title
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Phase I/II Trial of CPX-351 + Palbociclib in Patients With Acute Myeloid Leukemia

Conditions
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AML, Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Palcociclib
* Drug: CPX-351


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed acute myeloid leukemia according to 2016 WHO criteria(excluding APL [AML-M3]). Eastern Cooperative Oncology Group (ECOG) Performance Status <2 Subjects must have normal organ function as defined below: Total bilirubin <2 times upper limit of normal ((≤ 3 x ULN if considered to be due to leukemic involvement or Gilbert's syndrome) or if higher than 2 times upper limit of normal with approval from the PI Serum Creatinine <2 x ULNor if higher than 2 times upper limit of normal with approval from the PI Left ventricular ejection fraction of ≥45% Patients with secondary AML arising out of MDS (all subtypes under WHO classification), chronic myelomonocytic leukemia (CMML) and therapy-related AML are eligible. Women of childbearing potential should be advised to avoid becoming pregnant and men should be advised to not father a child while receiving treatment. All men and women of childbearing potential must use acceptable methods of birth control throughout the study Subjects must have the ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: Prior treatment with CPX-351, Palbociclib or other cell cycle inhibitors. Any serious medical condition, laboratory abnormality, or psychiatric illness that, in the view of the treating physician, would place the participant at an unacceptable risk if he or she were to participate in the study or would prevent that person from giving informed consent. Any active malignancy (unrelated, non-hematological malignancy) diagnosed within the past 6 months of starting the study drug (other than curatively treated carcinoma-in-situ of the cervix or non-melanoma skin cancer). History of allergic reactions attributed to compounds of similar chemical or biologic composition to CPX-351, Palbociclib or other cell cycle inhibitors. Subjects with uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Known history of HIV or active hepatitis B or C. No major surgery within 2 weeks prior to study enrollment. Pregnancy or breast feeding Male and female patients who are fertile who do not agree to use an effective barrier methods of birth control (i.e. abstinence) to avoid pregnancy while receiving study treatment. Acute promyelocytic leukemia (APL)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: This is a single arm, open label study of the combination of Palbociclib with CPX-351 in adults with AML. The trial consists of two components: phase I to evaluate the safety with dose escalation of Palbociclib in combination with CPX-351 and phase II to evaluate the overall response rate of the combination in the targeted patient population. A cycle is 28 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib + CPX-351<br>Palbociclib will be administered orally on day -1 and -2 at 125 mg PO during the phase IIaportion (dose level 0).Day 0 will be rest and then CPX-351 at 100 u/m2 will be started on days 1, 3, and 5 along with Palbociclib day 2, 4, and 6 followed by rest/monitoring period (day 7-28). If Grade 3-4 non-hematologic toxicity is observed in 1 or less of 6 patients treated, the study will move to Phase IIb. If Grade 3-4 non-hematologic toxicity is observed in 2 or more of 6 patients treated, 6 additional patients will be treated on the Phase IIa portion at a lower dose level (100 mg po) until a Phase IIb safe dose schedule is defined at which 1 or less out of 6 patients on the Phase IIa experience Grade 3-4 non-hematologic toxicity. After the Phase IIa portion ensures safety, the study will proceed with phase IIb. The phase IIb component is a Simon 2-stage design trial whose objective is to assess the clinical efficacy of the combination of Palbociclib and CPX-351. | Drug: Palcociclib<br>* Palbociclib is an investigational (experimental) drug that works to induce early G1 arrest by inhibiting CDK4/6, which are two types of CDKs that are overexpressed in AML cell cancer lines. Palbociclib is experimental because it is not approved by the Food and Drug Administration (FDA). Palbociclib will be supplied as capsules or tablets containing 125 mg equivalents of Palbociclib free base<br>* Other names: IBRANCE;Drug: CPX-351<br>* CPX-351 (daunorubicin and cytarabine) liposome for injection is a combination of daunorubicin and cytarabine in a 1:5 molar ratio encapsulated in liposomes for intravenous administration. CPX-351 is an investigational (experimental) drug that works as formulation of a fixed combination of the antineoplastic drugs cytarabine and daunorubicin. CPX-351 is experimental because it is not approved by the Food and Drug Administration (FDA).<br>* Other names: VYXEOS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of experimental dose of Palbociclibin combination with CPX-351 as measured by number of participants with dose limiting toxicities. | If Grade 3-4 non-hematologic toxicity is observed in 1 or less of 6 patients treated, the dose of the study drug will be considered safe/tolerable. If Grade 3-4 non-hematologic toxicity is observed in 2 or more of 6 patients treated, 6 additional patients will be treated on the Phase IIa portion at a lower dose level (100 mg po). | Between days 28-35 of starting treatment | 
| Efficacy of Palbociclibin combination with chemotherapy as measured by overall response rate (ORR). | Efficacy of Palbociclibin combination with chemotherapy as measured by overall response rate (ORR) which is defined as complete response (CR) and CR with incomplete blood count recovery (CRi) by IWG criteria. Complete remission is defined as: Bone marrow blasts <5%; absence ofcirculating blasts and blasts with Auerrods; absence of extramedullarydisease; absolute neutrophil count >1.0x 109/L (1,000/μL); platelet count >100 x109/L (100,000/μL) and CR with incomplete blood count recovery is defined as: All CR criteria except for residualneutropenia [<1.0 x 109/L (1,000/μL)] orthrombocytopenia [<100 x 109/L(100,000/μL)]. Either of these responses will constitute ORR. | Up to 2 years from end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to response (TTR) | TTR measured between start of treatment and the date of achievement of response (responses defined per 2003 IWG criteria). | Up to 2 years from end of treatment | 
| Duration of response (DOR) | DOR is measured between the date of response to date of loss of response. | Up to 2 years from end of treatment | 
| Event-free survival (EFS) | EFS measured from the date of entry into a study to the date of primary refractory disease, or relapse from CR, or CRi, or death from any cause; patients not known to have any of these events are censored on the date they were last examined | Up to 2 years from end of treatment | 
| Overall Survival (OS) probability | OS probability measured from the date of entry into a clinical trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive | Up to 2 years from end of treatment |