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Male and female patients with excess blasts of 5% to 30% who meet all of the following criteria are eligible for enrollment in the trial:
a. 18-81 years of age
b. 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 <10% BM blasts)
- RAEB 2 (10% to <20% BM blasts)
- RAEB-t (20% to 30% BM blasts)
d. 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
e. Total duration of prior HMA therapy ≤ 9 months
f. Last dose of AZA or DAC within 6 months before the planned date of randomization; however, must be off these treatments for ≥ 4 weeks before randomization
g. Has failed to respond to, relapsed following, not eligible for, or opted not to participate in allogenic stem cell transplantation
h. 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
i. Patients with 5q- syndrome should have failed to respond to or progressed on treatment with lenalidomide
j. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (Appendix 6)
k. Willing to adhere to the prohibitions and restrictions specified in this protocol
l. Patients (or, in case of patients who are incapable, the patient’s legally authorized representative appointed earlier by the court) must sign an Informed Consent document in conjunction with the patient’s next of kin indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study. In cases where the patient is incapable of signing the Informed Consent document by him- or herself, both the legal representative and the next of kin must have reason to believe that it is the will of the patient to provide consent and participate in the study. However, should the patient in any manner indicate the will not to participate, or the will to withdraw participation, this takes precedence and must be respected. A patient incapable of giving Informed Consent must be exluded if one or more of the conditions mentioned under the last bullet point of the ‘Exclusion Criteria’ (Section 3.2.2, v) are met.
Patients with any of the following will not be enrolled in the study:
a. 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
b. 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)
c. Patient previously diagnosed with AML (defined as a bone marrow blast percentage of >30%)
d. 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.
e. Any active malignancy, except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast, must have been treated with an outcome of complete remission for at least five years
f. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure or unstable angina pectoris
g. Active infection not adequately responding to appropriate therapy
h. Total bilirubin ≥ 1.5 mg/dL not related to hemolysis or Gilbert’s disease
i. Alanine transaminase (ALT)/aspartate transaminase (AST) ≥ 2.5 x upper limit of normal (ULN)
j. Serum creatinine ≥ 2.0 mg/dL. Calculated GFR <60 mL/min.
Sweden specific requirement: Instead of serum creatinine, the estimated Glomerular Filtration Rate (eGFR) should be used to measure renal function. It is recommended to use eGFR calculators, e.g. that published by the US National Institute of Health (ICH)
https://www.niddk.nih.gov/health-information/health-communication-progra...). For example, a serum creatinine level of 2.0 mg/dL in a 70 year-old male, non African-American patient corresponds to 33 mL/min/m2 and in a 70 year-old female, non African-American patient to 25 mL/min m2, respectively.
Known HIV, hepatitis B or hepatitis C
k. Uncorrected hyponatremia (defined as serum sodium level of < 130 mEq/L)
l. Female patients of child-bearing potential (pre-menopausal and not surgically sterilized, Section 4.7.4) who are breast-feeding or have a positive blood beta-human chorionic gonadotropin (HCG) pregnancy test at Screening
m. Female patients of child-bearing potential and male patients with sexual partners of child-bearing potential who are unwilling to follow strict contraception requirements. Examples of acceptable contraception methods include:
- estrogen-gestagen based contraceptives associated with inhibitgion of ovulation (oral, intravaginal, transdermal),
- gestagen-only based contraceptives associated with inhibition of ovulation (oral, injectable, implantable),
- intra-uterine devices (IUDs),
- intra-uterine hormone-releasing systems (IUSs),
- bilateral tubal exclusion, and vasectomized partner
- sexual abstinence
Pregnancy testing (blood or human blood or urine beta-human chorionic gonadotropin [beta-HCG] pregnancy test) should be performed in female patients with reproductive potential at Screening, before entry and throughout the study at monthly intervals, up to and including the 30-day non-treatment follow-up period. Patients with positive beta-HCG pregnancy tests should be excluded from the study.
n. Major surgery without full recovery or major surgery within 3 weeks prior to planned randomization
o. Uncontrolled hypertension
p. New onset seizures (within 3 months prior to planned randomization) or poorly controlled seizures
q. Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy, or corticosteroids (prednisone up to 20 mg/day or its equivalent is permitted for chronic conditions)
r. Treatment with cytarabine at any dose, lenalidomide, or any other therapy targeted for the treatment of MDS (other than growth factors and other supportive care measures) within 4 weeks of planned randomization
s. Investigational therapy within 4 weeks of planned randomization
t. Psychiatric illness or social situation that would limit the patient’s ability to tolerate and/or comply with study requirements.
u. Patients incapable of giving Informed Consent who have the following conditions: aphasia (verbal GCS score < 5 and NIHSS score > 0), patients with dementia, patients with a reduced level of consciousness (GCS < 14, RLS > 1, NHSS total score > 1.