A Study of PRT1419 in Patients With Relapsed/Refractory Hematologic Malignancies

Phase 1

Completed

• Conditions: Multiple Myeloma; Acute Myeloid Leukemia; Non Hodgkin Lymphoma; Myelodysplastic Syndromes
• Interventions: Drug: PRT1419

• Registration Number: NCT04543305
• Lead Sponsor: Prelude Therapeutics

Brief Summary

This is a Phase 1 dose-escalation study of PRT1419, a myeloid cell leukemia 1 (MCL1) inhibitor, in patients with relapsed/refractory hematologic malignancies. The purpose of this study is to define the dosing schedule, maximally tolerated dose and/or estimate the optimal biological dose to be used in subsequent development of PRT1419.

Detailed Description

This is a multicenter, open-label, dose-escalation Phase 1 study of PRT1419, a MCL1 inhibitor, evaluating patients in two cohorts as part of a 28-day treatment cycle in adult patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), high-risk myelodysplastic syndrome (MDS) or MDS/myeloproliferative neoplasm (MPN) overlap syndrome. Cohort A will evaluate PRT1419 administered as monotherapy in patients with either AML, CMML and/or high-risk MDS or MDS/MPN overlap. Cohort B will evaluate PRT1419 administered as monotherapy in patients with NHL or MM. The study will employ a "3+3" dose escalation design. The dose may be escalated until a dose limiting toxicity is identified.

Study Timeline

• Study First Submitted: 2020-09-02
• Study First Submitted QC: 2020-09-02
• Study First Posted: 2020-09-10
• Study Start: 2020-09-28
• Primary Completion: 2022-03-21
• Study Completion: 2022-03-21
• Status Verified: 2022-11
• Last Update Submitted: 2022-11-14
• Last Update Posted: 2022-11-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 16

Inclusion Criteria

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

• Adequate organ function (bone marrow, hepatic, renal, cardiovascular)

• Left ventricular ejection fraction of ≥50%

• 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

• Patients must have recovered from the effects of any prior cancer related therapy, radiotherapy or surgery (toxicity ≤ 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 study entry

• 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

  • White blood cell count < 25 x 10^9/L. Hydrea 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 prior therapy with a hypomethylating agent.

• MDS patients only: Intermediate, high, or very high risk by International Prognostic Scoring System-Revised [IPSS-R] criteria that is relapsed or refractory to approved therapies or MDS/MPN Overlap Syndrome (displaying both fibrosis and dysplastic features).

• NHL patients only: Histologically or cytologically confirmed NHL, including B- and T-cell lymphomas that is relapsed or refractory or intolerant to approved therapies. Must have one lesion that can be measured for response

• MM patients only: Measurable disease defined by one or more of the following: Serum M-protein ≥ 0.5 g/dL, Urine M-protein ≥ 200 mg/24 hours, Serum Free Light Chain (sFLC) > 10 mg/dL with normal serum FLC ratio. Presence of soft tissue plasmacytoma confirmed by imaging

• NHL and MM patients only: must have the following lab values within 14 days prior to study Day 1:

  • ANC ≥1.0 x 10^3 μL
  • Platelet count ≥50,000 μL

Exclusion Criteria

• Known hypersensitivity to any of the components of PRT1419

• Female patients who are pregnant or lactating

• Mean QTcF interval of >480 msec

• History of heart failure, additional risk factors for arryhthmias or requiring concomitant medications that prolong the QT/QTc interval

• Hematopoietic stem-cell transplant < 90 days or have GVHD Grade >1 at study entry

• Uncontrolled intercurrent illnesses

• Treatment with strong inhibitors of CYP2C8 and/or P-glycoprotein for which there are no therapeutic substitutions

• Inflammatory disorders of the gastrointestinal tract, or subjects with GI malabsorption

• HIV positive; known active hepatitis B or C

• Prior exposure to an MCL1 inhibitor

• History of another malignancy except:

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
PRT1419	PRT1419	PRT1419 will be administered orally

Primary Outcome Measures

Name	Time	Method
To determine the maximally tolerated dose (MTD) and/or optimal biological dose (OBD)	Baseline through approximately 2 years	The MTD and/or OBD will be established for further investigation in participants with multiple myeloma, Non-Hodgkin's Lymphoma, acute myeloid leukemia and myelodysplastic syndrome
To determine the recommended phase 2 dose (RP2D) and schedule of PRT1419	Baseline through approximately 2 years	The RP2D will be established for further investigation in participants with multiple myeloma, Non-Hodgkin's Lymphoma, acute myeloid leukemia and myelodysplastic syndrome
To describe dose limiting toxicities (DLT) of PRT1419	Baseline through Day 28	Dose limiting toxicities will be evaluated through the first cycle

Secondary Outcome Measures

Name	Time	Method
To describe the pharmacokinetic profile of PRT1419	Baseline through approximately 2 years	PRT1419 pharmacokinetics will be calculated including the maximum observed plasma concentration
To describe the adverse event profile and tolerability of PRT1419	Baseline through approximately 2 years	Adverse events as characterized by type, frequency, severity, timing, seriousness and relationship to study therapy
To describe any anti-tumor activity of PRT1419	Baseline through approximately 2 years	Anti-tumor activity of PRT1419 will be based on the measurement of objective responses

Trial Locations

Locations (4)

The University of Texas MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Florida Cancer Specialists; 🇺🇸 Sarasota, Florida, United States

Colorado Blood Cancer Institute; 🇺🇸 Denver, Colorado, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States