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

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ClinicalTrials.gov Identifier: NCT02407080
Recruitment Status : Completed
First Posted : April 2, 2015
Last Update Posted : September 12, 2019
Sponsor:
Collaborators:
Roche Pharma AG
The Leukemia and Lymphoma Society
Information provided by (Responsible Party):
John Mascarenhas, Icahn School of Medicine at Mount Sinai

Study Description
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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.


Condition or disease Intervention/treatment Phase
Polycythemia Vera Essential Thrombocythemia Drug: RG7388 Drug: Pegasys Phase 1

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Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open Label Phase I Study of Single Agent Oral RG7388 in Patients With Polycythemia Vera and Essential Thrombocythemia (With Pilot Feasibility Study in Combination With Pegylated Interferon Alfa 2a for Patients Who do Not Respond to the Single Agent at Each Dose Level)
Study Start Date : April 2015
Actual Primary Completion Date : December 19, 2018
Actual Study Completion Date : December 19, 2018

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Arms and Interventions
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Arm Intervention/treatment
Experimental: RG7388

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

Drug: Pegasys
PEGASYS is supplied as a clear, sterile solution for subcutaneous (SQ) injection available in prefilled syringes. weekly doses at 45ug subcutaneously
Other Name: pegylated interferon alfa-2a


Outcome Measures
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Primary Outcome Measures :
  1. The dose limiting toxicity of RG7388 [ Time Frame: up to 56 days ]
  2. The dose limiting toxicity of combination of RG7388 and Pegasys [ Time Frame: up to 2 years ]

Secondary Outcome Measures :
  1. Hematologic response of PR + CR by modified ELN response criteria [ Time Frame: up to 2 years ]
  2. Molecular response by percent reduction in baseline JAK2V617F allele burden [ Time Frame: up to 2 years ]
  3. Changes in bone marrow histopathologic abnormalities [ Time Frame: up to 2 years ]
  4. Reduction in baseline reticulin/collagen fibrosis [ Time Frame: up to 2 years ]
  5. Incidence of venous and arterial thrombosis [ Time Frame: up to 2 years ]
  6. Changes in MPN related symptoms as measured by the MPN-SAF [ Time Frame: up to 2 years ]

Other Outcome Measures:
  1. Pre-treatment wild type P53 status and MDM2 levels as predictors of response to therapy [ Time Frame: baseline ]
  2. Changes in mRNA levels of the following biomarkers : • MIC-1, PCNA, CDKN1A/p21, GDF15, TNFRSF10B/TRAIL-R2, TP53I3/PIG3, and GADD45 [ Time Frame: baseline and 2 years ]
  3. 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 [ Time Frame: baseline ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

(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.

Exclusion Criteria:

  • 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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02407080


Locations
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United States, District of Columbia
Georgetown University Medical Center
Washington, District of Columbia, United States, 20007
United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
United States, North Carolina
Wake Forest University Baptist Medical Center
Winston-Salem, North Carolina, United States, 27157
Sponsors and Collaborators
John Mascarenhas
Roche Pharma AG
The Leukemia and Lymphoma Society
Investigators
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Study Chair: John Mascarenhas, MD Icahn School of Medicine at Mount Sinai
Study Chair: Ronald Hoffman, MD Icahn School of Medicine at Mount Sinai
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: John Mascarenhas, Associate Professor, Icahn School of Medicine at Mount Sinai
ClinicalTrials.gov Identifier: NCT02407080     History of Changes
Other Study ID Numbers: GCO 12-0481-1001
MPD-RC 115 ( Other Identifier: Myeloproliferative Disorders-Research Consortium )
GCO 14-1919 ( Other Identifier: Icahn School of Medicine at Mount Sinai )
First Posted: April 2, 2015    Key Record Dates
Last Update Posted: September 12, 2019
Last Verified: September 2019
Additional relevant MeSH terms:
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Polycythemia Vera
Polycythemia
Thrombocytosis
Thrombocythemia, Essential
Hematologic Diseases
Bone Marrow Neoplasms
Hematologic Neoplasms
Neoplasms by Site
Neoplasms
Bone Marrow Diseases
Myeloproliferative Disorders
Blood Platelet Disorders
 Blood Coagulation Disorders
Hemorrhagic Disorders
Interferons
Interferon-alpha
Interferon alpha-2
Peginterferon alfa-2a
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunologic Factors
Physiological Effects of Drugs