Open Label Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia

NCT02407080 | Completed Phase 1 DMC

• 3 other identifiers: GCO 12-0481-1001MPD-RC 115GCO 14-1919
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 3

Brief Summary

This research looks at two conditions, Essential Thrombocythemia (ET) and Polycythemia Vera (PV). ET causes people to produce too many blood cells called platelets and PV causes too many platelets and red blood cells to be made. Platelets are particles which circulate in the blood stream and normally prevent bleeding and bruising. Having too many platelets in the blood increases the risk of developing blood clots, which can result in life threatening events like heart attacks and strokes. When the number of red blood cells is increased in PV this will slow the speed of blood flow in the body and increase the risk of developing blood clots. The purpose of Part A of this study is to test the safety and tolerability of drug RG7388 patients and identify the recommended phase II dose in a single agent dose escalation study. The investigators want to find out what effects, good and/or bad it has on the disease. The purpose of Part B of this study is to test the safety and tolerability of the combination of RG7388 and Pegylated Interferon Alfa-2a or Pegasys in PV/ET patients from Part A who did not achieve at least a partial response by the end of three cycles of single agent RG7388. Essential Thrombocythemia (ET) and Polycythemia Vera (PV) have been difficult diseases to treat. RG7388 is a selective inhibitor of the p53-MDM2 binding that frees p53 from negative control and activates the p53 pathway in cancer cells, leading to cell cycle arrest and apoptosis in vitro and in vivo. It has been used to treat solid tumors and Acute Myelogenous Leukemia (AML) in clinical trials. Pegasys is a drug that is the standard of care for patients who have Chronic Hepatitis B (CHB). RG7388 is a drug that is not yet approved by the Federal Drug Administration (FDA) for the treatment of patients with essential thrombocythemia or polycythemia vera. Pegasys is a drug that is approved by the FDA for the treatment of CHB. The use of RG7388 alone and in combination with Pegasys is experimental.

Conditions

Polycythemia Vera; Essential Thrombocythemia

Outcome Measures

Primary Outcomes (2)

• The dose limiting toxicity of RG7388

  up to 56 days

• The dose limiting toxicity of combination of RG7388 and Pegasys

  up to 2 years

Secondary Outcomes (6)

• Hematologic response of PR + CR by modified ELN response criteria

  up to 2 years

• Molecular response by percent reduction in baseline JAK2V617F allele burden

  up to 2 years

• Changes in bone marrow histopathologic abnormalities

  up to 2 years

• Reduction in baseline reticulin/collagen fibrosis

  up to 2 years

• Incidence of venous and arterial thrombosis

  up to 2 years

Other Outcomes (3)

• Pre-treatment wild type P53 status and MDM2 levels as predictors of response to therapy

  baseline

• Changes in mRNA levels of the following biomarkers : • MIC-1, PCNA, CDKN1A/p21, GDF15, TNFRSF10B/TRAIL-R2, TP53I3/PIG3, and GADD45

  baseline and 2 years

• Pre-treatment wild type P53 status and MDM2 levels as predictors of response to combination therapy who failed RG7388 alone and were subsequently treated with combination therapy

  baseline

Study Arms (1)

RG7388

EXPERIMENTAL

Part A: RG7388 as a single agent; given at a starting dose of 100 mg each day for five days for the first cycle which will be 56 days. Part B: combination of RG7388 and Pegasys if subject does not achieve at least a PR by the end of 3 cycles of single agent RG7388

Drug: RG7388; Drug: Pegasys

Interventions

RG7388 DRUG

RG7388 is supplied as film-coated tablets at dosage strengths of 50 mg, 200 mg, 300mg and 400 mg.

RG7388

Pegasys DRUG

PEGASYS is supplied as a clear, sterile solution for subcutaneous (SQ) injection available in prefilled syringes. weekly doses at 45ug subcutaneously

Also known as: pegylated interferon alfa-2a

RG7388

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• (Patient should meet all the criteria)
• JAK2V617F-positive PV or JAK2V617F-positive ET (confirmed by WHO diagnostic criteria)
• High risk ET/PV \[age \>60; history of thrombosis\] or low risk disease with symptoms \[recurrent headaches, paresthesias, pruritus\]
• Previously treated with at least one other agent \[hydroxyurea, interferon, anagrelide\] and determined to be either intolerant/resistant
• ≥18 years of age
• Eastern Cooperative Oncology Group (ECOG) Performance status 0-2
• Acceptable pre-study organ function during screening as defined as: Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) unless due to Gilbert's disease or hemolysis, Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times ULN, Serum creatinine ≤ 1.5 x ULN
• Women of childbearing potential and males must agree to use adequate contraception (i.e., hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a female subject become pregnant or suspect she is pregnant while participating in this study, she should inform the treating physician immediately
• Ability to understand and willingness to sign a written informed consent document.

You may not qualify if:

• Meets the criteria for post ET/PV MF as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
• Blast phase disease (\>20% blasts in the marrow or peripheral blood)
• Acute thrombosis within 3 months of screening
• Uncontrolled intercurrent illness including, but not limited to hepatitis, human immunodeficiency virus (HIV) - positive subjects receiving combination antiretroviral therapy, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, ventricular arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Sponsors & Collaborators

• John Mascarenhas: lead
• Roche Pharma AG: collaborator
• The Leukemia and Lymphoma Society: collaborator

Study Sites (3)

Georgetown University Medical Center

Washington D.C., District of Columbia, 20007, United States

Location

Icahn School of Medicine at Mount Sinai

New York, New York, 10029, United States

Location

Wake Forest University Baptist Medical Center

Winston-Salem, North Carolina, 27157, United States

Location

Related Publications (1)

• Mascarenhas J, Lu M, Kosiorek H, Virtgaym E, Xia L, Sandy L, Mesa R, Petersen B, Farnoud N, Najfeld V, Rampal R, Dueck A, Hoffman R. Oral idasanutlin in patients with polycythemia vera. Blood. 2019 Aug 8;134(6):525-533. doi: 10.1182/blood.2018893545. Epub 2019 Jun 5.

  PMID: 31167802 DERIVED

MeSH Terms

Conditions

Polycythemia Vera; Thrombocythemia, Essential

Interventions

RG7388; peginterferon alfa-2a

Condition Hierarchy (Ancestors)

Bone Marrow Neoplasms; Hematologic Neoplasms; Neoplasms by Site; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Myeloproliferative Disorders; Blood Coagulation Disorders; Thrombocytosis; Blood Platelet Disorders; Hemorrhagic Disorders

Study Officials

• John Mascarenhas, MD

  Icahn School of Medicine at Mount Sinai

  STUDY CHAIR

• Ronald Hoffman, MD

  Icahn School of Medicine at Mount Sinai

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: March 24, 2015
• First Posted: April 2, 2015
• Study Start: April 1, 2015
• Primary Completion: December 19, 2018
• Study Completion: December 19, 2018
• Last Updated: September 12, 2019

Record last verified: 2019-09

Locations

US (3)