Clinical trial NCT05107856: 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
Overall status: TERMINATED
Phase: PHASE1
Conditions: 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
Lead sponsor: Prelude Therapeutics
Sponsor class: INDUSTRY
First posted: 2021-11-04
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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:

  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

Primary outcomes:
measure: Dose limiting toxicities (DLT) of PRT1419
timeFrame: Baseline through Day 28
measure: Safety and tolerability of PRT1419: AEs, SAEs, CTCAE assessments
timeFrame: Baseline through approximately 3 years
measure: Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) and schedule of PRT1419
timeFrame: Baseline through approximately 2 years
Secondary outcomes:
measure: Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: maximum observed plasma concentration
timeFrame: Baseline through approximately 3.5 years
measure: Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: Time to maximal plasma concentration
timeFrame: Baseline through approximately 3.5 years
measure: Pharmacokinetic profile of PRT1419 monotherapy and in combination with AZA or VEN: Area under the curve
timeFrame: Baseline through approximately 3.5 years
measure: Safety and tolerability of PRT1419 in combination with AZA and VEN: AEs, SAEs, CTCAE assessments
timeFrame: Baseline through approximately 3 years
measure: Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Overall response rate (ORR)
timeFrame: Baseline through approximately 3.5 years
measure: Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Progression-free survival (PFS)/event free survival (EFS)
timeFrame: Baseline through approximately 3.5 years
measure: Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Duration of response (DOR)
timeFrame: Baseline through approximately 3.5 years
measure: Anti-tumor activity of PRT1419 monotherapy and in combination with AZA and VEN: Overall survival (OS)
timeFrame: Baseline through approximately 3.5 years
Other outcomes:
Locations:
city: Orange City
country: United States
facility: Mid Florida Hematology and Oncology Center
state: Florida
city: Orlando
country: United States
facility: AdventHealth Bone and Marrow Transplant Center
state: Florida
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland, PA
state: Maryland
city: Brick
country: United States
facility: New Jersey Center for Cancer Research
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center - Main Campus
state: New York
city: Port Jefferson Station
country: United States
facility: North Shore Hematology Oncology Associates. DBA New York Cancer and Blood Specialists
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: Philadelphia
country: United States
facility: Thomas Jefferson University, Sidney Kimmel Cancer Center
state: Pennsylvania
city: Houston
country: United States
facility: The University of Texas MD Anderson Cancer Center
state: Texas
Study officials:
References: