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

• ClinicalTrials.gov Identifier: NCT01926587
• Recruitment Status: Completed
• First Posted: August 21, 2013
• Last Update Posted: June 16, 2021
• Sponsor: Onconova Therapeutics, Inc.
• Information provided by (Responsible Party): Onconova Therapeutics, Inc.

Study Description

Brief Summary:

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 or disease	Intervention/treatment	Phase
Myelodysplastic Syndrome; Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia	Drug: oral rigosertib; Drug: Azacitidine	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Allocation: N/A
• 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
• Study Start Date: August 2013
• Actual Primary Completion Date: December 8, 2020
• Actual Study Completion Date: February 16, 2021

Arms and Interventions

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 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

Outcome Measures

Primary Outcome Measures :

1. 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.
2. 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.
3. 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.
4. 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.
5. 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 :

1. 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.
2. 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• 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

Locations

United States, Arizona

Banner MD Anderson Cancer Center

Gilbert, Arizona, United States, 85234

United States, California

City of Hope

Duarte, California, United States, 91010

Desert Hematology Oncology Medical Group, Inc.

Rancho Mirage, California, United States, 92270

United States, Illinois

Rush University Medical Center

Chicago, Illinois, United States, 60612

United States, Kansas

Cancer Center of Kansas

Wichita, Kansas, United States, 67214

United States, Missouri

Saint Louis University

Saint Louis, Missouri, United States, 63110

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

Mount Sinai Medical Center

New York, New York, United States, 10029

White Plains Hospital Center for Cancer Care

White Plains, New York, United States, 10601

United States, South Carolina

Carolina Blood and Cancer Care Associates

Rock Hill, South Carolina, United States, 29732

United States, Texas

The University of Texas MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Wisconsin

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

France

Hôpital St. Louis

Paris, France, 75475

Sponsors and Collaborators

Onconova Therapeutics, Inc.

Investigators

• Study Chair: Steven M. Fruchtman, MD; Onconova Therapeutics, Inc.

More Information

Additional Information:

Information about clinical trials at MD Anderson Cancer Center 

Publications of Results:

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.

Other Publications:

Navada SC, Silverman LR. The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes. Expert Rev Anticancer Ther. 2016 Aug;16(8):805-10. doi: 10.1080/14737140.2016.1209413. Epub 2016 Jul 15.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Navada SC, Garcia-Manero G, OdchimarReissig R, Pemmaraju N, Alvarado Y, Ohanian MN, John RB, Demakos EP, Zbyszewski PS, Maniar M, Woodman RC, Fruchtman SM, Silverman LR. Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study. Leuk Res. 2020 Jul;94:106369. doi: 10.1016/j.leukres.2020.106369. Epub 2020 May 12.

• Responsible Party: Onconova Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT01926587
• Other Study ID Numbers: Onconova 09-08; 2013-000673-72 ( EudraCT Number )
• First Posted: August 21, 2013
• Last Update Posted: June 16, 2021
• Last Verified: June 2021

Keywords provided by Onconova Therapeutics, Inc.:

rigosertib; ON 01910.Na; azacitidine; Vidaza

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile; Myelodysplastic Syndromes; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Azacitidine; ON 01910; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors; Protein Kinase Inhibitors