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

Primary Purpose

Acute Myeloid Leukemia, B-cell Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PRT1419
Azacitidine
Venetoclax
Sponsored by
Prelude Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring 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

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 to 2
  • Adequate organ function (bone marrow, hepatic, renal, cardiovascular)
  • Left ventricular ejection fraction of ≥ 50%
  • All patients must have recovered from the effects of any prior cancer related therapy, radiotherapy, or surgery (toxicity no greater than Grade 1).
  • All patients on prior investigational agents must wait at least 5 half-lives of the agent in question, or 14 days, whichever is longer before enrollment into the trial, and until any toxicities of the prior investigational agent have resolved to Grade 1 or a baseline state
  • Female patients of childbearing potential must have a negative pregnancy test within 7 days of the start of treatment and must agree to use a highly effective method of contraception during the trial
  • AML patients only: Pathologically confirmed diagnosis of AML as defined by the WHO Classification and patients with targeted mutations must have been treated with appropriate therapy for their disease

    a. White blood cell count < 25 × 10^9/L. Hydroxyurea or leukapheresis are permitted to meet this criterion

  • CMML patients only: intermediate-2 or high risk per CMML-specific prognostic scoring system (CPSS) or clinical/molecular CPSS (CPSS-mol) criteria. Must have failed at least 4-6 cycles of prior therapy with a hypomethylating agent
  • High Risk MDS - MDS/MPN Overlap Syndrome: intermediate, high, or very high risk by International Prognostic Scoring System-Revised [IPSS-R] criteria that is relapsed or refractory to approved therapies, including at least 4-6 cycles of a hypomethylating agent, or MDS/MPN Overlap Syndrome (displaying both fibrosis and dysplastic features)

Exclusion Criteria:

  • Known hypersensitivity to any of the components of PRT1419
  • Female patients who are pregnant or lactating
  • Active inflammatory disorders of the gastrointestinal tract, or patients with GI malabsorption
  • Mean QTcF interval of > 480 msec
  • History of heart failure, additional risk factors for arrhythmias or requiring concomitant medications that prolong the QT/QTc interval
  • Elevated cardiac troponin or evidence of recent cardiac injury
  • HIV positive; known active hepatitis B or C
  • Hematopoietic stem-cell transplantation within the last 90 days or have GVHD Grade > 1 at study entry
  • Uncontrolled intercurrent illnesses
  • Treatment with either OATP1B1, OATP1B3 substrates or strong inhibitors of CYP2C8
  • Prior exposure to an MCL1 inhibitor
  • History of another malignancy except for:

    1. Malignancy treated with curative intent with no known active disease for > 2 years prior to study start
    2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
    3. Adequately treated carcinoma in situ without evidence of disease
    4. Other concurrent low-grade malignancies (i.e., chronic lymphocytic leukemia (CLL) (Rai 0)) may be considered after consultation with Sponsor

Sites / Locations

  • Mid Florida Hematology and Oncology CenterRecruiting
  • AdventHealth Bone and Marrow Transplant CenterRecruiting
  • American Oncology Partners of Maryland, PARecruiting
  • New Jersey Center for Cancer ResearchRecruiting
  • Memorial Sloan Kettering Cancer Center - Main CampusRecruiting
  • North Shore Hematology Oncology Associates. DBA New York Cancer and Blood SpecialistsRecruiting
  • Gabrail Cancer Center ResearchRecruiting
  • Thomas Jefferson University, Sidney Kimmel Cancer CenterRecruiting
  • The University of Texas MD Anderson Cancer CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

PRT1419 Monotherapy

PRT1419/Azacitidine Combination

PRT1419/Venetoclax Combination

Arm Description

PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned.

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.

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.

Outcomes

Primary Outcome Measures

Dose limiting toxicities (DLT) of PRT1419
Dose limiting toxicities will be evaluated over the 28-day observation period
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)
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

Secondary Outcome Measures

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
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)
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)
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)
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
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
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
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

Full Information

First Posted
October 25, 2021
Last Updated
March 31, 2023
Sponsor
Prelude Therapeutics
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1. Study Identification

Unique Protocol Identification Number
NCT05107856
Brief Title
PRT1419 as Monotherapy or in Combination With Azacitidine or Venetoclax in R/R Myeloid or B-cell Malignancies
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 22, 2022 (Actual)
Primary Completion Date
May 2025 (Anticipated)
Study Completion Date
November 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Prelude Therapeutics

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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
Keywords
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
132 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
PRT1419 Monotherapy
Arm Type
Experimental
Arm Description
PRT1419 will be administered by intravenous infusion once weekly on a 28-day treatment cycle at the dose level assigned.
Arm Title
PRT1419/Azacitidine Combination
Arm Type
Experimental
Arm Description
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.
Arm Title
PRT1419/Venetoclax Combination
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
PRT1419
Intervention Description
PRT1419 will be administered by intravenous infusion
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
Azacitidine will be administered by intravenous or subcutaneous
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Intervention Description
Venetoclax will be administered orally
Primary Outcome Measure Information:
Title
Dose limiting toxicities (DLT) of PRT1419
Description
Dose limiting toxicities will be evaluated over the 28-day observation period
Time Frame
Baseline through Day 28
Title
Safety and tolerability of PRT1419: AEs, SAEs, CTCAE assessments
Description
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)
Time Frame
Baseline through approximately 3 years
Title
Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) and schedule of PRT1419
Description
The MTD/RP2D will be established for further investigation in participants with advanced hematologic malignancies
Time Frame
Baseline through approximately 2 years
Secondary Outcome Measure Information:
Title
Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: maximum observed plasma concentration
Description
PRT1419 pharmacokinetics will be calculated by maximum observed plasma concentration
Time Frame
Baseline through approximately 3.5 years
Title
Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: Time to maximal plasma concentration
Description
PRT1419 pharmacokinetics will be calculated by time to maximal plasma concentration (Tmax)
Time Frame
Baseline through approximately 3.5 years
Title
Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: Area under the curve
Description
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)
Time Frame
Baseline through approximately 3.5 years
Title
Safety and tolerability of PRT1419 in combination with AZA and VEN: AEs, SAEs, CTCAE assessments
Description
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)
Time Frame
Baseline through approximately 3 years
Title
Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Overall response rate (ORR)
Description
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
Time Frame
Baseline through approximately 3.5 years
Title
Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Progression-free survival (PFS)/event free survival (EFS)
Description
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
Time Frame
Baseline through approximately 3.5 years
Title
Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Duration of response (DOR)
Description
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
Time Frame
Baseline through approximately 3.5 years
Title
Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Overall survival (OS)
Description
Duration from Day 1 until death due to any cause
Time Frame
Baseline through approximately 3.5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Study Contact (Please Do Not Disclose Personal Information)
Phone
See Email
Email
PRT1419-03IVstudy@preludetx.com
Facility Information:
Facility Name
Mid Florida Hematology and Oncology Center
City
Orange City
State/Province
Florida
ZIP/Postal Code
32763
Country
United States
Individual Site Status
Recruiting
Facility Name
AdventHealth Bone and Marrow Transplant Center
City
Orlando
State/Province
Florida
ZIP/Postal Code
32804
Country
United States
Individual Site Status
Recruiting
Facility Name
American Oncology Partners of Maryland, PA
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20817
Country
United States
Individual Site Status
Recruiting
Facility Name
New Jersey Center for Cancer Research
City
Brick
State/Province
New Jersey
ZIP/Postal Code
08724
Country
United States
Individual Site Status
Recruiting
Facility Name
Memorial Sloan Kettering Cancer Center - Main Campus
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Individual Site Status
Recruiting
Facility Name
North Shore Hematology Oncology Associates. DBA New York Cancer and Blood Specialists
City
Port Jefferson Station
State/Province
New York
ZIP/Postal Code
11776
Country
United States
Individual Site Status
Recruiting
Facility Name
Gabrail Cancer Center Research
City
Canton
State/Province
Ohio
ZIP/Postal Code
44718
Country
United States
Individual Site Status
Recruiting
Facility Name
Thomas Jefferson University, Sidney Kimmel Cancer Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Individual Site Status
Recruiting
Facility Name
The University of Texas MD Anderson Cancer Center
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Learn more about this trial

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

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