Safety Study of ALRN-6924 in Patients With Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome

Study Overview
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Brief Summary
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Phase 1/1b, open label, multi-center dose escalation and dose expansion study designed to evaluate safety, tolerability, PK (pharmacokinetics), PD (pharmacodynamics) and anti-tumor effects of ALRN-6924 alone or in combination with cytarabine in patients with relapsed/refractory acute myeloid leukemia or advanced myelodysplastic syndrome with wild-type (WT) TP53

Detailed Description
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Phase I, open label, multi-center dose escalation (DEP) and dose expansion (EXP) study designed to evaluate safety, tolerability, PK (pharmacokinetics), PD (pharmacodynamics) and anti-tumor effects of ALRN-6924 in patients with acute myeloid leukemia or advanced myelodysplastic syndrome with wild-type (WT) TP53. ALRN-6924 is a stabilized cell-permeating peptide designed to disrupt interaction between the p53 tumor suppression protein and its endogenous inhibitors murine double minute 2 (MDM2) and murine double minute X (MDMX) Men and women 18 years of age and older with relapsed or refractory acute myeloid leukemia or advanced myelodysplastic syndrome and for which standard treatment(s) are not available or are no longer effective can be enrolled. Treatment of patients in the DEP and EXP phases will continue in the study until documentation of disease progression, unacceptable toxicity, or patient or physician decision to discontinue study participation is made.

Official Title
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A Phase 1/1b Open-Label Study to Determine the Safety and Tolerability of ALRN-6924 Alone and in Combination With Cytarabine (Ara-C) in Patients With Relapsed/Refractory Acute Myeloid Leukemia or Advanced Myelodysplastic Syndrome With Wild-Type TP53

Conditions
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Acute Myeloid Leukemia, Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: ALRN-6924
* Drug: ALRN-6924 in combination with cytarabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory acute myeloid leukemia or IPSS-R intermediate/high/very high-risk MDS patients Confirmed or anticipated wild-type TP53 ECOG (Eastern Cooperative Oncology Group) performance status 0-2 Adequate hepatic and renal function Acceptable coagulation function Negative serum or urine pregnancy test within 7 days prior to the first dose of ALRN-6924 for women of child-bearing potential Sufficient wash out from prior therapies and recovery from all significant toxicities Exclusion Criteria: Patients are eligible for available approved standard therapies Prior treatment with MDM2 inhibitor, with protocol specified exceptions Patients with history of allogeneic stem cell transplantation Leukemic blast counts of >25,000/µl Deletion of chromosome 17, or del(17p) Patients with evidence of current central nervous system leukemic involvement Known hypersensitivity to any study drug component History of coagulopathy Prior specified cardiovascular risk factors Clinically significant gastrointestinal bleeding within 6 months Clinically significant third-space fluid accumulation Pregnant or lactating females Evidence of any serious and/or unstable pre-existing medical condition that would interfere with patient safety ability to provide informed consent Active uncontrolled infection, including HIV/AIDS or Hepatitis B or C Second malignancy within one year, with protocol specified exceptions

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALRN-6924<br>Fixed dose of ALRN-6924 per cohort, administered IV, Days 1, 8, and 15 every 28 days | Drug: ALRN-6924<br>* Fixed dose of ALRN-6924 per cohort, administered IV, Days 1, 8, and 15 every 28 days.<br>|
| Experimental: ALRN-6924 in combination with cytarabine<br>Cytarabine (100 or 200 mg/m2) will be administered as an IV infusion followed by ALRN-6924 on Days 1, 8, and 15 every 28 days. | Drug: ALRN-6924 in combination with cytarabine<br>* Cytarabine (100 or 200 mg/m2) will be administered as an IV infusion followed by ALRN-6924 on Days 1, 8, and 15 every 28 days.<br>* Other names: ALRN-6924 in combination with Ara-C;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the safety and tolerability of ALRN-6924 alone and in combination with cytarabine | Number of participants with treatment-related adverse events as assessed by CTCAE v.4.0 | From Day 1 of treatment until 30 days after the last cycle of treatment (each cycle is 28 days) | 
| Determine maximum tolerated dose (MTD) | Determine the dose limiting toxicities (DLT) and the maximum tolerated dose (MTD) or the optimal biological dose (OBD) of ALRN-6924 in adult patients with AML or MDS | From the first dose until the end of Cycle 2 (each cycle is 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine PK parameters of ALRN-6924 when administered to patients with acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS) | Peak Plasma Concentration (Cmax) | First 2 cycles (each cycle is 28 days) | 
| Determine PK parameters of ALRN-6924 when administered to patients with acute myeloid leukemia (AML) or advanced myelodysplastic syndrome (MDS) | Area under the plasma concentration versus time curve [AUC] | First 2 cycles (each cycle is 28 days) | 
| Determine immunogenicity of ALRN-6924 | Incidence of anti-ALRN-6924 antibodies | Approximately 16 weeks | 
| Determine best overall response, duration of response, morphologic leukemia-free state, leukemia free survival, percentage of MDA patients who have achieved hematologic improvement, changes in transfusion rate and early death rate | International Working Group (IWG) Criteria (Cheson et al, 2006) | Approximately 16 weeks | 
| Determine best overall response, duration of response, morphologic leukemia-free state, leukemia free survival, percentage of MDA patients who have achieved hematologic improvement, changes in transfusion rate and early death rate | AML response criteria (Dohner et al, 2010) | Approximately 16 weeks | 
| Determine best overall response, duration of response, morphologic leukemia-free state, leukemia free survival, percentage of MDA patients who have achieved hematologic improvement, changes in transfusion rate and early death rate | International Working Group (IWG) Criteria for hematological improvement in MDS (Cheson et al, 2000) | Approximately 16 weeks |