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

This study is currently recruiting participants.
Verified November 2017 by Onconova Therapeutics, Inc.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01926587
First Posted: August 21, 2013
Last Update Posted: November 17, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
Onconova Therapeutics, Inc.
  Purpose
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.

Condition Intervention Phase
Myelodysplastic Syndrome Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia Drug: oral rigosertib Drug: Azacitidine Phase 1 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Onconova Therapeutics, Inc.:

Primary Outcome Measures:
  • 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.

  • 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.

  • 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.

  • 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.

  • 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.


Secondary Outcome Measures:
  • 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.

  • 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.


Estimated Enrollment: 40
Study Start Date: August 2013
Estimated Study Completion Date: October 2018
Estimated Primary Completion Date: June 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Vidaza

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.

  Eligibility

Information from the National Library of Medicine

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

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.
  Contacts and Locations
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): NCT01926587


Contacts
Contact: Joseph Morgan, MD (267) 759-3680 jmorgan@onconova.us
Contact: Steven M. Fruchtman, MD (267) 759-3680 sfruchtman@onconova.us

Locations
United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Principal Investigator: Samer Khaled, MD         
Desert Hematology Oncology Medical Group, Inc. Recruiting
Rancho Mirage, California, United States, 92270
Principal Investigator: David E. Young, MD         
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Principal Investigator: Jamile Shammo, MD         
United States, Kansas
Cancer Center of Kansas Recruiting
Wichita, Kansas, United States, 67214
Principal Investigator: Shaker R. Dakhil, MD         
United States, Missouri
Saint Louis University Recruiting
Saint Louis, Missouri, United States, 63110
Principal Investigator: M. Nabeel Rajeh, MD         
United States, New York
Roswell Park Cancer Institute Recruiting
Buffalo, New York, United States, 14263
Principal Investigator: Elizabeth Griffiths, MD         
Mount Sinai Medical Center Recruiting
New York, New York, United States, 10029
Principal Investigator: Shyamala Navada, MD         
White Plains Hospital Center for Cancer Care Recruiting
White Plains, New York, United States, 10601
Principal Investigator: Dan Costin, MD         
United States, South Carolina
Carolina Blood and Cancer Care Associates Recruiting
Rock Hill, South Carolina, United States, 29732
Principal Investigator: Sashi Naidu, MD         
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Principal Investigator: Guillermo Garcia-Manero, MD         
United States, Wisconsin
Froedtert Hospital and the Medical College of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Principal Investigator: Ehab Atallah, MD         
France
Hôpital St. Louis Completed
Paris, France, 75475
Sponsors and Collaborators
Onconova Therapeutics, Inc.
Investigators
Study Chair: Steven M. Fruchtman, MD Onconova Therapeutics, Inc.
  More Information

Additional Information:
Publications:
Garcia-Manero G, Fenaux P. Comprehensive Analysis of Safety: Rigosertib in 557 Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML). Blood Dec 2016, 128 (22) 2011; ASH 2016.
Navada S, Garcia-Manero G. Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study. Blood Dec 2016, 128 (22) 3167; ASH 2016.
Navada, S. et al. Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS). Leukemia Research , Volume 55 , S30, April 2017; MDS 2017.
Chaurasia, P. et al. Rigosertib in Combination with Azacitidine Modulates Epigenetic Pathways and can Overcome Clinical Resistance to Hypomethylating Agents in Myelodysplastic Syndromes (MDS). Leukemia Research , Volume 55 , S121, April 2017; MDS 2017.

Responsible Party: Onconova Therapeutics, Inc.
ClinicalTrials.gov Identifier: NCT01926587     History of Changes
Other Study ID Numbers: Onconova 09-08
2013-000673-72 ( EudraCT Number )
First Submitted: August 18, 2013
First Posted: August 21, 2013
Last Update Posted: November 17, 2017
Last Verified: November 2017

Keywords provided by Onconova Therapeutics, Inc.:
rigosertib
ON 01910.Na
azacitidine
Vidaza

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Leukemia, Myelomonocytic, Chronic
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Myelodysplastic-Myeloproliferative Diseases
Azacitidine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors