Phase II Part 2 Expansion of Oral Rigosertib in Combination With Azacitidine

June 15, 2021 updated by: Onconova Therapeutics, Inc.

A Phase I/II, Multi-center, Dose-escalating Study of the Tolerability, Pharmacokinetics, and Clinical Activity of the Combined Administration of Oral Rigosertib With Azacitidine in Patients With Myelodysplastic Syndrome or Acute Myeloid Leukemia

This study, is a Phase I/II clinical trial in three parts: Phase I Dose Escalation, Phase II, Part 1 RPTD Cohort, and Phase II, Part 2 Expansion. The first two parts have been completed. The Phase II, Part 2 Expansion will assess if treatment with rigosertib in combination with azacitidine, has measurable effects in patients with myelodysplastic syndrome (MDS). Safety of patients is an objective throughout all parts of the study.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This will be a Phase I/II open-label, single-arm, dose-escalating, multicenter study, in three parts: Phase I Dose Escalation, Phase II, Part 1 RPTD Cohort, and Phase II, Part 2 Expansion, in which patients with myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML) will receive subcutaneous (SC) or intravenous (IV) azacitidine per approved label in combination with oral rigosertib. The first two parts of the study have been completed.

The Phase II Part 2 Expansion will enroll up to 40 patients, randomized 1:1 into 2 cohorts of up to 20 patients each, to receive 1120 mg of rigosertib over 24 hours: either 560 mg in the morning and 560 mg in the afternoon, or 840 mg in the morning and 280 mg in the afternoon. The afternoon dose in both cohorts must be administered at 3 PM (±1 hr) at least 2 hr after lunch. In the Phase II, Part 2 Expansion patients with RAEB t/non-proliferative AML will be eligible, however patients with CMML will not.

Study Type

Interventional

Enrollment (Actual)

45

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France, 75475
        • Hopital St. Louis
  • United States
    • Arizona
      • Gilbert, Arizona, United States, 85234
        • Banner MD Anderson Cancer Center
    • California
      • Duarte, California, United States, 91010
        • City of Hope
      • Rancho Mirage, California, United States, 92270
        • Desert Hematology Oncology Medical Group, Inc.
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Rush University Medical Center
    • Kansas
      • Wichita, Kansas, United States, 67214
        • Cancer Center of Kansas
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Saint Louis University
    • New York
      • Buffalo, New York, United States, 14263
        • Roswell Park Cancer Institute
      • New York, New York, United States, 10029
        • Mount Sinai Medical Center
      • White Plains, New York, United States, 10601
        • White Plains Hospital Center for Cancer Care
    • South Carolina
      • Rock Hill, South Carolina, United States, 29732
        • Carolina Blood and Cancer Care Associates
    • Texas
      • Houston, Texas, United States, 77030
        • The University of Texas Md Anderson Cancer Center
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Froedtert Hospital and the Medical College of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Diagnosis of MDS, CMML, or RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ≤ 25,000 x 10^9/L and stable for at least 4 weeks without intervention) according to World Health Organization (WHO) criteria or French American British (FAB) classification either previously treated or previously untreated. The diagnosis must be confirmed via BM aspirate and/or biopsy within 6 weeks prior to Screening. Note: patients with RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ≤ 25,000 x 10^9/L and stable for at least 4 weeks without intervention) are not eligible for the Phase II Part 1 RPTD component of the study and patients with CMML will not be eligible for Phase II Part 2 Expansion of the study.
  • If the patient has been diagnosed with MDS, disease of patient must be classified as Int-1, Intermediate-2 (Int-2) or High-risk, according to International Prognosis Scoring System (IPSS) classification. Note: Only Int-2 or High-risk patients will be enrolled at French site.
  • Off all other treatments for MDS, CMML, or AML including an erythropoiesis-stimulating agent (ESA), for at least 4 weeks prior to Screening. Filgrastim (G-CSF) is allowed before and during the study, as clinically indicated.
  • For AML patients, no more than 1 prior salvage therapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
  • Willing to adhere to the prohibitions and restrictions specified in this protocol.
  • The patient must signed an informed consent form indicating that she/he understands the purpose of and procedures required for the study and is willing to participate in the study.

Exclusion Criteria:

  • Prior treatment with rigosertib;
  • Anemia due to factors other than MDS, CMML, or AML (including hemolysis or gastrointestinal bleeding).
  • Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast.
  • Uncontrolled intercurrent illness.
  • Active infection not adequately responding to appropriate therapy.
  • Total bilirubin ≥ 2.0 mg/dL not related to Gilbert's disease or hemolysis.
  • Alanine transaminase (ALT)/aspartate transaminase (AST) ≥ 2.5 x upper limit of normal (ULN).
  • Serum creatinine ≥ 2.0 mg/dL.
  • Ascites requiring active medical management including paracentesis.
  • Hyponatremia (defined as serum sodium value of < 130 mEq/L).
  • Female patients who are pregnant or lactating.
  • Female patients of childbearing potential and male patients with partners of childbearing potential who are unwilling to follow strict contraception requirements before entry and throughout the study, up to and including the 30-day nontreatment follow-up period.
  • Female patients with reproductive potential who do not have a negative blood or urine pregnancy test at Screening.
  • Major surgery without full recovery or major surgery within 3 weeks of Screening.
  • Uncontrolled hypertension (defined as a systolic pressure ≥ 160 mmHg and/or a diastolic pressure ≥ 110 mmHg).
  • New onset seizures (within 3 months prior to Screening) or poorly controlled seizures.
  • Any other investigational agent or chemotherapy, radiotherapy, or immunotherapy administered within 4 weeks prior to Screening.
  • Chronic use (˃ 2 weeks) of corticosteroids (˃ 10 mg/24 hr equivalent prednisone) within 4 weeks of Baseline/First Dose.
  • Investigational therapy within 4 weeks of Screening.
  • Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.
  • Patients with RAEB-t/non-proliferative AML (as defined by 20-30% BMBL, WBC ≤ 25,000 x 10^9/L and stable for at least 4 weeks without intervention) are not eligible to participate in the Phase II Part 1 RPTD component of the study and patients with CMML will not be eligible for Phase II Part 2 of the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Oral rigosertib plus azacitidine
Oral rigosertib will be administered twice a day in fasting conditions for weeks 1, 2, and 3 of a 4-week cycle. Starting on Day 1 of second week (Day 8) of the cycle, azacitidine will be administered by subcutaneous injection or intravenous infusion at the labeled daily dose of 75 mg/m2, for 7 days.
Drug: oral rigosertib
Oral rigosertib will be administered twice a day in fasting conditions for weeks 1, 2, and 3 of a 4-week cycle.
Other Names:
  • ON 01910.Na
Drug: Azacitidine
Starting on Day 1 of second week (Day 8) of the cycle, azacitidine will be administered by subcutaneous injection or intravenous infusion at the labeled daily dose of 75 mg/m2, for 7 days.
Other Names:
  • Vidaza

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Dose escalation part of study: Number of patients in whom Dose a Limiting Toxicity (DLT) are observed
Time Frame: 28 days
Dose Limiting Toxicity is defined as Grade 3 or greater non-hematological toxicity or stomatitis and/or esophagitis/dysphagitis lasting longer than 3 days.
28 days
Dose escalation part of study: Number of patients in whom adverse events are observed
Time Frame: Up to 48 weeks
Adverse events will be coded using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class (SOC), preferred term (PT), and worst Common Terminology Criteria for Adverse Events (CTCAE) Version 4 grade per patient.
Up to 48 weeks
In Phase 2 of study: Number of patients in whom adverse events are observed
Time Frame: Up to 48 weeks
Adverse events will be coded using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by system organ class (SOC), preferred term (PT), and worst Common Terminology Criteria for Adverse Events (CTCAE) Version 4 grade per patient.
Up to 48 weeks
In Phase 2 of study: Area Under the Curve (AUC)
Time Frame: Day 1 and Day 15
The following time points will be used to collect samples to determine the AUC on Day 1 and 15: Pre-dose the first dose of the day and at 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, and 8.0 hour post dose the first dose of the day.
Day 1 and Day 15
In Phase 2 of the study: Cmax
Time Frame: Days 1 and 15.
The following time points will be used to collect samples to determine the Cmax on Day 1 and 15: Pre-dose the first dose of the day and at 0.5, 1.0, 1.5, 2.0, 4.0, 6.0, and 8.0 hour post dose the first dose of the day.
Days 1 and 15.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of patients with complete or partial response
Time Frame: Up to 48 weeks
Complete remission (CR) or partial remission (PR) or bone marrow CR according to 2006 International Working Group criteria.
Up to 48 weeks
Number of patients in whom improvements in absolute neutrophil count, platelet count, and erythroid responses are observed
Time Frame: Up to 48 weeks.
Hematologic Improvement according to 2006 International Working Group criteria.
Up to 48 weeks.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Onconova Therapeutics, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

August 1, 2013

Primary Completion (Actual)

December 8, 2020

Study Completion (Actual)

February 16, 2021

Study Registration Dates

First Submitted

August 18, 2013

First Submitted That Met QC Criteria

August 20, 2013

First Posted (Estimate)

August 21, 2013

Study Record Updates

Last Update Posted (Actual)

June 16, 2021

Last Update Submitted That Met QC Criteria

June 15, 2021

Last Verified

June 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Onconova 09-08
  • 2013-000673-72 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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