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

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

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).

Study Overview

• Status: Terminated
• Conditions: Follicular Lymphoma; Acute Myeloid Leukemia; Myelodysplastic Syndromes; Chronic Myelomonocytic Leukemia; Mantle Cell Lymphoma; Marginal Zone Lymphoma; Chronic Lymphocytic Leukemia; Myeloproliferative Neoplasm; Small Lymphocytic Lymphoma; B-cell Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: PRT1419; Drug: Azacitidine; Drug: Venetoclax

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Orange City, Florida, United States, 32763
      • Mid Florida Hematology and Oncology Center
    • Orlando, Florida, United States, 32804
      • AdventHealth Bone and Marrow Transplant Center
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners of Maryland, PA
  • New Jersey
    • Brick, New Jersey, United States, 08724
      • New Jersey Center for Cancer Research
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center - Main Campus
    • Port Jefferson Station, New York, United States, 11776
      • North Shore Hematology Oncology Associates. DBA New York Cancer and Blood Specialists
  • Ohio
    • Canton, Ohio, United States, 44718
      • Gabrail Cancer Center Research
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University, Sidney Kimmel Cancer Center
  • Texas
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

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:

  1. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  2. Adequately treated cervical or breast carcinoma in situ without evidence of disease
  3. 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
  4. Other malignancy treated with curative intent with no known active disease for > 2 years prior to enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PRT1419 Monotherapy; PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned.	Drug: PRT1419; PRT1419 will be administered by intravenous infusion
Experimental: PRT1419/Azacitidine Combination; 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; PRT1419 will be administered by intravenous infusion; Drug: Azacitidine; Azacitidine will be administered by intravenous or subcutaneous
Experimental: PRT1419/Venetoclax Combination; 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; PRT1419 will be administered by intravenous infusion; Drug: Venetoclax; Venetoclax will be administered orally

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Prelude Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): March 22, 2022
• Primary Completion (Actual): January 19, 2024
• Study Completion (Actual): January 19, 2024

Study Registration Dates

• First Submitted: October 25, 2021
• First Submitted That Met QC Criteria: October 25, 2021
• First Posted (Actual): November 4, 2021

Study Record Updates

• Last Update Posted (Actual): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 29, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Follicular Lymphoma; Marginal Zone Lymphoma; Venetoclax; Azacitidine; Chronic lymphocytic leukemia (CLL); Small lymphocytic lymphoma (SLL); Mantle Cell Lymphoma; Acute Myeloid Leukemia (AML); Hematologic Malignancies; Myelodysplastic Syndromes (MDS); B-cell Malignancies; Chronic Myelomonocytic Leukemia (CMML); Myeloproliferative Neoplasm (MPN); B-cell Non-Hodgkin lymphoma; Myeloid cell leukemia-1 (MCL-1); PRT1419; Relapsed/Refractory Myeloid
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Leukemia, B-Cell; Chronic Disease; Neoplasms; Lymphoma; Lymphoma, Follicular; Lymphoma, B-Cell; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Myeloproliferative Disorders; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Venetoclax; Azacitidine
• Other Study ID Numbers: PRT1419-03

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No