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

NCT01926587 | Completed Phase 1

• 2 other identifiers: Onconova 09-082013-000673-72
• Study Type: interventional
• Target: 45
• Locations: 2 countries
• Sites: 13

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.

Conditions

Myelodysplastic Syndrome; Acute Myeloid Leukemia; Chronic Myelomonocytic Leukemia

Keywords

rigosertib; ON 01910.Na; azacitidine; Vidaza

Outcome Measures

Primary Outcomes (5)

• Dose escalation part of study: Number of patients in whom Dose a Limiting Toxicity (DLT) are observed

  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

  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

  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)

  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

  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 Outcomes (2)

• Number of patients with complete or partial response

  Up to 48 weeks

• Number of patients in whom improvements in absolute neutrophil count, platelet count, and erythroid responses are observed

  Up to 48 weeks.

Study Arms (1)

Oral rigosertib plus azacitidine

EXPERIMENTAL

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; Drug: Azacitidine

Interventions

oral rigosertib DRUG

Oral rigosertib will be administered twice a day in fasting conditions for weeks 1, 2, and 3 of a 4-week cycle.

Also known as: ON 01910.Na

Oral rigosertib plus azacitidine

Azacitidine DRUG

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.

Also known as: Vidaza

Oral rigosertib plus azacitidine

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Traws Pharma, Inc.: lead

Study Sites (13)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

City of Hope

Duarte, California, 91010, United States

Location

Desert Hematology Oncology Medical Group, Inc.

Rancho Mirage, California, 92270, United States

Location

Rush University Medical Center

Chicago, Illinois, 60612, United States

Location

Cancer Center of Kansas

Wichita, Kansas, 67214, United States

Location

Saint Louis University

St Louis, Missouri, 63110, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

Mount Sinai Medical Center

New York, New York, 10029, United States

Location

White Plains Hospital Center for Cancer Care

White Plains, New York, 10601, United States

Location

Carolina Blood and Cancer Care Associates

Rock Hill, South Carolina, 29732, United States

Location

The University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Hôpital St. Louis

Paris, 75475, France

Location

Related Publications (6)

• 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.

  PMID: 27400247 BACKGROUND

• 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.

  BACKGROUND

• 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.

  RESULT

• 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.

  RESULT

• 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.

  RESULT

• 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.

  PMID: 32442785 DERIVED

Related Links

• Information about clinical trials at MD Anderson Cancer Center

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic

Interventions

ON 01910; Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Steven M. Fruchtman, MD

  Traws Pharma, Inc.

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 18, 2013
• First Posted: August 21, 2013
• Study Start: August 1, 2013
• Primary Completion: December 8, 2020
• Study Completion: February 16, 2021
• Last Updated: June 16, 2021

Record last verified: 2021-06

Locations

FR (1); US (12)