PRT1419 as Monotherapy or in Combination With Azacitidine or Venetoclax in R/R Myeloid or B-cell Malignancies

Study Overview
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Brief Summary
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This is a Phase 1 dose-escalation study of PRT1419, a myeloid cell leukemia-1 (MCL-1) inhibitor, in participants with selected relapsed/refractory myeloid or B-cell malignancies. The purpose of this study is to evaluate the safety and tolerability of PRT1419 monotherapy and in combination with either azacitidine or venetoclax, describe any dose limiting toxicities (DLTs), define the dosing schedule, and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D).

Detailed Description
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This is a multicenter, open-label, dose-escalation, Phase 1 study of PRT1419, a MCL-1 inhibitor, evaluating participants with acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm (MPN) overlap syndrome, chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), and B-cell non-hodgkin lymphoma (NHL) including marginal zone lymphoma, follicular lymphoma or mantle cell lymphoma. Participants in study will receive PRT1419 as monotherapy or in combination with either Azacitidine (AZA) or Venetoclax (VEN). The study includes multiple dose escalations and expansion cohorts for RP2D confirmation.

Official Title
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A Phase 1, Open-Label, Multicenter, Dose Escalation Study of PRT1419 Injection as Monotherapy or in Combination With Azacitidine or Venetoclax in Patients With Relapsed/Refractory Myeloid or B-cell Malignancies

Conditions
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Acute Myeloid Leukemia, B-cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, Chronic Myelomonocytic Leukemia, Follicular Lymphoma, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Myelodysplastic Syndromes, Myeloproliferative Neoplasm, Small Lymphocytic Lymphoma

Intervention / Treatment
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* Drug: PRT1419
* Drug: Azacitidine
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations (including contraception requirements), and other study procedures Refractory/relapsed disease, having progressed on prior treatment, and without access to further approved therapies or ineligible for approved therapies, in one of the following disease categories: AML, CMML, MDS, MDS/MPN Overlap Syndrome, CLL/SLL, and B-cell NHLs Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 to 2 Adequate organ function (hematology, hepatic, renal, and coagulation) Exclusion Criteria: Active inflammatory disorders of the gastrointestinal tract, a history of bariatric surgery or other disorders with the potential for GI malabsorption Cardiac function compromise, as assessed by echocardiogram or protocol-specified biochemical markers of cardiac damage, or protocol-defined clinically significant heart disease History of cerebrovascular accident or transient ischemic attack, within 6 months of screening. Participants with a history of pulmonary embolism must not be symptomatic at enrollment Undergone hematopoietic stem-cell transplantation (HSCT) within the last 90 days or have graft-versus-host disease (GVHD) Grade > 1 at study entry Uncontrolled intercurrent illnesses, poorly controlled hypertension or dyslipidemias, Unstable central nervous system (CNS) metastases Treatment with either OATP1B1, OATP1B3 substrates or strong inhibitors of CYP2C8, CYP3A4, and any medication contraindicated in combination with AZA or VEN Prior exposure to an MCL-1 inhibitor Within 5 half-lives or 14 days (whichever is longer) following the last systemic anti-cancer therapy History of another malignancy except for: Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated cervical or breast carcinoma in situ without evidence of disease Asymptomatic prostate cancer without known metastatic disease and no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for >1 year prior to enrollment Other malignancy treated with curative intent with no known active disease for > 2 years prior to enrollment

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRT1419 Monotherapy<br>PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned. | Drug: PRT1419<br>* PRT1419 will be administered by intravenous infusion<br>|
| Experimental: PRT1419/Azacitidine Combination<br>PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned and Azacitidine will be administered by intravenous or subcutaneous on Days 1 through 7 (or alternatively on Days 1 through 5, 8 and 9) of each 28-day treatment cycle. | Drug: PRT1419<br>* PRT1419 will be administered by intravenous infusion<br>Drug: Azacitidine<br>* Azacitidine will be administered by intravenous or subcutaneous<br>|
| Experimental: PRT1419/Venetoclax Combination<br>PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned and Venetoclax will be administered orally after either a 3-day or 5-week ramp-up period to reach 400 mg daily administration, prior to commencing PRT1419 administration. | Drug: PRT1419<br>* PRT1419 will be administered by intravenous infusion<br>Drug: Venetoclax<br>* Venetoclax will be administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities (DLT) of PRT1419 | Dose limiting toxicities will be evaluated over the 28-day observation period | Baseline through Day 28 | 
| Safety and tolerability of PRT1419: AEs, SAEs, CTCAE assessments | Safety and tolerability will be assessed by recording adverse events (AEs), serious adverse events (SAEs), and DLTs according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Baseline through approximately 3 years | 
| Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) and schedule of PRT1419 | The MTD/RP2D will be established for further investigation in participants with advanced hematologic malignancies | Baseline through approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: maximum observed plasma concentration | PRT1419 pharmacokinetics will be calculated by maximum observed plasma concentration | Baseline through approximately 3.5 years | 
| Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: Time to maximal plasma concentration | PRT1419 pharmacokinetics will be calculated by time to maximal plasma concentration (Tmax) | Baseline through approximately 3.5 years | 
| Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: Area under the curve | PRT1419 pharmacokinetics will be calculated by area under the plasma concentration x time curve (AUC) from h 0 to the last measurable time point (AUC0-last) | Baseline through approximately 3.5 years | 
| Safety and tolerability of PRT1419 in combination with AZA and VEN: AEs, SAEs, CTCAE assessments | Safety and tolerability will be assessed by recording adverse events (AEs), serious adverse events (SAEs), and DLTs according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) | Baseline through approximately 3 years | 
| Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Overall response rate (ORR) | Anti-tumor activity of PRT1419 based on the measurement of objective response rate (ORR) according to the disease-specific response criteria for malignancies under study | Baseline through approximately 3.5 years | 
| Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Progression-free survival (PFS)/event free survival (EFS) | Duration from Day 1 to the earliest date of first disease progression, as assessed by the investigator according to the disease-specific response criteria for malignancies under study, or death due to any cause | Baseline through approximately 3.5 years | 
| Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Duration of response (DOR) | Duration from time of first observed response (CR or PR) to the earliest date of disease progression, as assessed by the investigator according to the disease-specific response criteria for malignancies under study, or death due to any cause | Baseline through approximately 3.5 years | 
| Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Overall survival (OS) | Duration from Day 1 until death due to any cause | Baseline through approximately 3.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Myeloid Leukemia (AML), Azacitidine, B-cell Malignancies, B-cell Non-Hodgkin lymphoma, Chronic lymphocytic leukemia (CLL), Chronic Myelomonocytic Leukemia (CMML), Follicular Lymphoma, Hematologic Malignancies, Mantle Cell Lymphoma, Marginal Zone Lymphoma, Myelodysplastic Syndromes (MDS), Myeloid cell leukemia-1 (MCL-1), Myeloproliferative Neoplasm (MPN), PRT1419, Relapsed/Refractory Myeloid, Small lymphocytic lymphoma (SLL), Venetoclax