Study of BMN 673, a PARP Inhibitor, in Patients With Advanced Hematological Malignancies

Phase 1, Two-arm, Open-label Study Of Once Daily, Oral Bmn 673 In Patients With Advanced Hematological Malignancies

This is a two-arm, open-label study to determine the maximum tolerated dose (MTD) and assess the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of BMN 673 in patients with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL). Arm 1 will enroll patients with either AML or MDS; Arm 2 will enroll patients with either CLL or MCL.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia; Mantle Cell Lymphoma; Chronic Lymphocytic Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Drug: BMN 673

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom, SE5 9RS
    • King's College Hospital
  • London, United Kingdom, NW1 2BU
    • University College London
  • Manchester, United Kingdom, M20 4BX
    • The Christie NHS Foundation
  • Newcastle upon Tyne, United Kingdom, NE1 7RU
    • University of Newcastle Upon Tyne, NHS Foundation Trust
• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University Simon Cancer Center
  • Washington
    • Seattle, Washington, United States, 98109-1023
      • Seattle Cancer Care Alliance
  • Wisconsin
    • Madison, Wisconsin, United States, 53715
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. 18 years of age or older.
2. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
3. Arm 1 AML/MDS: Must have available tissue
4. Arm 2 CLL/MCL: Must have available tissue

5. Have adequate organ function as defined below:

   1. Serum aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 X upper limit of normal (ULN);
   2. Total serum bilirubin ≤ 1.5 X ULN;
6. Able to take oral medications
7. Recovered from acute toxicity of prior treatment
8. Willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.
9. If sexually active, must be willing to use an acceptable method of contraception during therapy and for 30 days after the last dose of BMN 673.
10. If female of childbearing potential, must have a negative serum pregnancy test at screening and be willing to have additional pregnancy tests during the study.
11. Willing and able to comply with all study procedures.

Exclusion Criteria:

1. Acute promyelocytic leukemia, APL [AML with t(15;17)(q22;q12), PML-RARA and variants].

2. Disease-specific exclusion criteria:

   a. AML: i. Marrow cellularity < 25% ii. Circulating blasts > 50,000/mm3 b. MCL and CLL: i. Platelet count < 50,000/mm3 ii. Neutrophil count < 1000/mm3

3. Autologous bone marrow transplant < 6 months before Cycle 1 Day 1
4. Prior allogeneic bone marrow transplant < 6 months before Cycle 1 Day 1 and/or with the presence of graft versus host disease (GVHD)

5. Prior treatment:

   1. AML: anti-leukemia treatment within 14 days before Cycle 1 Day 1; hydroxyurea treatment within 7 days before Cycle 1 Day 1.
   2. CLL, MCL or MDS: anti-lymphoma/leukemia treatment within 28 days before Cycle 1 Day 1;
6. CLL/MCL patients who have received transfusion, hematopoietic growth factors within 7 days before Cycle 1 Day 1.
7. Symptomatic central nervous system (CNS) involvement.
8. Known to have human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV).
9. Major surgery within 28 days before Cycle 1, Day 1.
10. Active peptic ulcer disease.
11. Active gastrointestinal tract disease with malabsorption syndrome.
12. Requirement for IV alimentation.
13. Prior surgical procedures affecting absorption.
14. Uncontrolled inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis).
15. Myocardial infarction within 6 months before Cycle 1 Day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or unstable cardiac arrhythmia requiring medication.
16. Breastfeeding at screening or planning to become pregnant (self or partner) at any time during study participation.
17. Use of any investigational product or investigational medical device within 28 days before Cycle 1, Day 1.

18. Concurrent disease or condition that would interfere with study participation or safety, such as:

    1. CLL/MCL patients with active, clinically significant infection requiring the use of parenteral anti-microbial agents, or grade > 2 infection by NCI CTCAE (v4.03) within 14 days before Cycle 1, Day 1(AML/MDS patients with controlled infection are eligible for the study with no specific time requirement prior to Cycle 1, Day 1);
    2. Clinically significant bleeding diathesis or coagulopathy, including known platelet function disorders;
    3. Non-healing wound, ulcer, or bone fracture.
19. Patients who have received prior treatment with a PARP inhibitor are not eligible for Part 2 of the study (expansion), but are eligible for Part 1 (dose escalation) of the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: BMN 673; Arm 1 will enroll patients with either AML or MDS	Drug: BMN 673; Oral capsule with multiple dosage forms given once daily
Experimental: Arm 2: BMN 673; Arm 2 will enroll patients with either CLL or MCL	Drug: BMN 673; Oral capsule with multiple dosage forms given once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The primary outcome of this study is to determine the MTD of daily oral BMN 673 in patients with AML and MDS (Arm 1) and patients with CLL and MCL (Arm 2).	Assessed after each visit until completion (Estimated duration is 12-18 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with adverse events		Assessed after each visit until completion of the study (Estimated duration is 24-30 months)
Determine the pharmacokinetic (PK) profile of BMN 673	Sample collection times vary per visit. PK parameters that will be evaluated include: maximum concentration (Cmax), minimum concentration (Cmin), time to maximum plasma concentration (Tmax), area under the curve from 0 to last quantifiable sampling point postdose (AUC0-inf), area under the curve extrapolated to infinity (AUC0-last), half life (t1/2), systemic clearance (CL/f) and volume of ditribution (VZ/f)	Assessed at each visit in cycle 1 - 5 (Estimated duration is 24 months)
Determine the Recommended Phase 2 Dose (RP2D) of oral daily BMN 673		Assessed after each visit until completion of the study (Estimated duration is 24-30 months)
Assess preliminary efficacy of BMN 673 by evaluating per response publications		Assessed approximately every 4-12 weeks (Estimated duration is 24-30 months)

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: Medivation, Inc.

Publications and helpful links

General Publications

• Gopal AK, Popat R, Mattison RJ, Menne T, Bloor A, Gaymes T, Khwaja A, Juckett M, Chen Y, Cotter MJ, Mufti GJ. A Phase I trial of talazoparib in patients with advanced hematologic malignancies. Int J Hematol Oncol. 2021 Oct 22;10(3):IJH35. doi: 10.2217/ijh-2021-0004. eCollection 2021 Sep.

Study record dates

Study Major Dates

• Study Start (Actual): June 30, 2011
• Primary Completion (Actual): March 31, 2014
• Study Completion (Actual): May 31, 2014

Study Registration Dates

• First Submitted: July 13, 2011
• First Submitted That Met QC Criteria: July 19, 2011
• First Posted (Estimate): July 22, 2011

Study Record Updates

• Last Update Posted (Actual): September 15, 2017
• Last Update Submitted That Met QC Criteria: September 14, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Neoplasms by Site; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Leukemia, B-Cell; Lymphoma; Myelodysplastic Syndromes; Hematologic Neoplasms; Leukemia; Lymphoma, Mantle-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Poly(ADP-ribose) Polymerase Inhibitors; Talazoparib
• Other Study ID Numbers: PRP-002; 2010-023964-42 (EudraCT Number); C3441022 (Other Identifier: Alias Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Information relating to our policy on data sharing and the process for requesting data can be found at the following link: http://www.pfizer.com/research/clinical_trials/trial_data_and_results/data_requests