Protocol Summary

Protocol No.: OCR14834

Sponsor Protocol No.: 04-30

Study Title
A Phase III, International, Randomized, Controlled Study of Rigosertib versus Physicians Choice of Treatment in Patients with Myelodysplastic Syndrome after Failure of a Hypomethylating Agent

Principal Investigator(s)
Cogle, Christopher

Objective
The study's goal is to compare the effectiveness of rigosertib in treating MDS.

Description
This is a Phase III, open-label, randomized, controlled, international study. Approximately 225 patients
Very high risk (VHR) vs non-VHR per IPSS-R, and
Geographic region (North America vs Europe vs Asia; because approved products and standard of care may vary by region), and randomly assigned in a 2:1 ratio to one of the following 2 treatment groups:
Rigosertib 1800 mg/24 hr administered as a 72 hr CIV infusion on Days 1, 2, and 3 of a 2 week cycle for the first 8 cycles, and on Days 1, 2, and 3 of a 4-week cycle thereafter (N = approximately 150 patients);
Physician's Choice of alternative treatment, which may include any approved or standard-of-care therapy that the patient has not shown to be hypersensitive to, based on frequently used treatment for MDS, as per institutional guidelines, after receipt of HMAs (N = approximately 75 patients). The drugs used in the Physician's Choice arm should be used according to the recommendations, if clinically appropriate, provided in the corresponding Summary of Product Characteristics (SmPC) and Prescribing Information of these drugs. Experimental therapies are not allowed on the PC arm.
Patients will be treated until 2006 IWG progression criteria are met (ie, 50% increase of BM blasts or worsening of cytopenias) or until an unacceptable toxicity or intolerance.

For all randomized patients who discontinue study treatment, subsequent therapies with their start and end dates, as well as survival time after treatment discontinuation, will be documented at least monthly until death.

Patients in the PC group who progress will not be allowed to cross over to rigosertib.

All patients in both treatment groups will be allowed, as medically justified, access to RBC and platelet transfusions and to growth factors (granulocyte colony-stimulating factor (G-CSF), erythropoietin, and thrombopoietin).

Phase: Phase III

Age Group: Adult

Scope: National

Treatment
Experimental: rigosertib + best supportive care (BSC)
- intravenous rigosertib 1800 mg/24 hr for 3 days every 2 weeks for first 8 cycles, then every 4 weeks thereafter + best supportive care (BSC).

Active Comparator: Physician's Choice (PC) + best supportive care (BSC)
- Physician's Choice of Treatment or alternative treatment which may include any approved or standard-of-care therapy, based on frequently used treatment for MDS (no experimental therapy) + best supportive care.

Detailed Eligibility
INCLUSION CRITERIA:
1. 18-81 years of age
2. MDS classification and cytogenetics confirmed within 8 weeks prior to or during screening as follows, according to WHO criteria (Appendix 2) or modified FAB classification (Appendix 3):
- RAEB-1 (5% to - RAEB-2 (10% to - RAEB-t (20% to 30% BM blasts)
3. At least one cytopenia (ANC L or platelet count L or hemoglobin [Hgb] 4 Progression (according to 2006 IWG criteria; Appendix 1) at any time after initiation of AZA or DAC treatment
or
Failure to achieve complete or partial response or HI (according to 2006 IWG) after at least six 4-week cycles of AZA or either four 4-week or four 6-week cycles of DAC
or
Relapse after initial complete or partial response or HI (according to 2006 IWG criteria)
or
Intolerance to AZA or DAC
5. Total duration of prior HMA therapy =6. Last dose of AZA or DAC within 6 months before the planned date of randomization; however, must be off htese treatments for >= 4 weeks before randomization
7. Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogenic stem cell transplantation
8. Off all other treatments for MDS (including AZA and DAC) for 4 weeks before randomization, with the exception that growth factors (G-CSF, erythropoietin, and TPO) and transfusions are allowed before and during the study as clinically indicated
9. Patients with 5q- syndrome should have failed to respond to or progressed on treatment
with lenalidomide, where available and indicated
10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2
11. Willing to adhere to the prohibitions and restrictions specified in this protocol
12. Patient must sign an Informed Consent form indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study. In case a patient is incapable of giving consent, the patients legally authorized representative (appointed earlier by the court) must give consent. However, should the patient in any manner indicate the will not to participate this takes precedence and must be
respected.

EXCLUSION CRITERIA:
1. Previous participation in a clinical study of IV or oral rigosertib; however, patients who failed screening for other rigosertib studies may be screened for participation in this study
2. Eligible to receive induction chemotherapy, such as 7-10 days of cytosine arabinoside and 2-3 days of an anthracycline, or high-dose cytarabine (HDAC)
3. Patient previously diagnosed with AML (defined as a bone marrow or peripheral blood blast percentage >30%)
4. Suitable candidate to receive allogeneic stem cell transplantation; patient is eligible for study if a suitable candidate refuses to undergo an allogeneic stem cell transplant or a suitable donor cannot be found
5. Any active malignancy within the past year, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast
6.. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris
7. Active infection not adequately responding to appropriate therapy
8. Total bilirubin >= 1.5 mg/dL not related to hemolysis or Gilberts disease
9. Alanine Transaminase (ALT)/aspartate transaminase (AST) >= 2.5 x upper limit of normal (ULN)
10. Serum creatinine >= 2.0 mg/dL or eGFR (estimated Glomerular Filtration Rate) 11. Known active HIV, hepatitis B or hepatitis C, where active is defined as follows:
- HIV or Hepatitis C presence of viral load
- Hepatitis B antigen positive
12. Uncorrected hyponatremia (defined as serum sodium level of
**Contact the study team for complete eligibility details.

Applicable Disease Sites

Myelodysplastic Syndrome (MDS)

Participating Institutions
UF Gainesville : Denise Praither

Contact
Denise Praither
Phone: +1 352-294-8713
Email: dpraithe@ufl.edu

More Information:
View study listing on ClinicialTrials.gov
http://www.clinicaltrials.gov/ct2/show/
NCT02562443