Efficacy and Safety of IV Rigosertib in MDS Patients With Excess Blasts Progressing After Azacitidine or Decitabine

Overview

About this study

This study will examine the effect intravenously administered rigosertib has on the relationship between bone marrow blasts response and overall survival in myelodysplastic syndromes (MDS) patients who have 5-30% bone marrow blasts and who progressed on or after treatment with azacitidine or decitabine.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Diagnosis of MDS confirmed within 6 weeks prior to Screening according to WHO criteria or French-American-British (FAB) classification.
  • MDS classified as follows, according to WHO criteria and FAB classification:
    • RAEB-1 (5% to 9% BM blasts)
    • RAEB-2 (10% to 19% BM blasts)
    • CMML (10% to 20% BM blasts) and white blood cells (WBC) < 13,000/μL
    • RAEB-t (20% to 30% BM blasts), meeting the following criteria: WBC < 25,000/μL at study entry; or, Stable White Blood Cell (WBC) at least 4 weeks prior to Screening and not requiring intervention for WBC control with hydroxyurea, chemotherapy, or leukopheresis.
  • At least one cytopenia (Absolute Neutrophil Count (ANC) < 1800/μL or Platelet (PLT) count < 100,000/μL or hemoglobin (Hgb) < 10 g/dL).
  • Progression (according to 2006 IWG criteria) at any time after initiation of subcutaneous or intravenous azacitidine or decitabine treatment per labeling during the past 2 years, defined as follows:
    • For patients with ˂ 5% BMBL, ≥ 50% increase in BMBL to ˃ 5% BMBL
    • For patients with 5-10% BMBL, ≥ 50% increase in BMBL to ˃ 10% BMBL
    • For patients with 10-20% BMBL, ≥ 50% increase in BMBL to ˃ 20% BMBL
    • For patients with 20-30% BMBL, ≥ 50% increase in BMBL to ˃ 30% BMBL
    • Any of the following: ≥ 50% decrease from maximum remission/response levels in granulocytes or PLT; Decrease in Hgb concentration by ≥ 2 g/dL; or, Transfusion dependence, defined as administration of at least 4 RBC units in the past 8 weeks before Screening (patients must have Hgb values ˂ 9 g/dL prior to transfusion to be considered), in the absence of another explanation.
  • Has failed to respond to, relapsed following, not eligible, or opted not to participate in bone marrow transplantation.
  • Off all other treatments for MDS for at least 4 weeks, except for azacitidine or decitabine. Filgrastim (G-CSF) and erythropoietin are allowed before and during the study as clinically indicated.
  • No medical need for induction chemotherapy.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
  • Willing to adhere to the prohibitions and restrictions specified in this protocol.
  • Patient must signed an informed consent form.

Exclusion Criteria:

  • Previous participation in a clinical study of IV or oral rigosertib.
  • Anemia due to factors other than MDS (including hemolysis or gastrointestinal [GI] bleeding) unless stabilized for 1 week after RBC transfusion.
  • 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 including.
  • Active infection not adequately responding to appropriate therapy.
  • Total bilirubin ≥ 1.5 mg/dL not related to hemolysis or Gilbert's disease.
  • ALT/AST ≥ 2.5 x upper limit of normal (ULN).
  • Serum creatinine ≥ 2.0 mg/dL.
  • Ascites requiring active medical management including paracentesis, or hyponatremia (defined as serum sodium value of <130 mEq/L).
  • Female patients who are pregnant or lactating.
  • Patients who are unwilling to follow strict contraception requirements.
  • Female patients with reproductive potential who do not have a negative urine beta-human chorionic gonadotropin (βHCG) pregnancy test at Screening.
  • Major surgery without full recovery or major surgery within 3 weeks of Baseline/Cycle 1 Day 1 visit.
  • Uncontrolled hypertension (defined as a systolic pressure ≥160 mmHg and/or a diastolic pressure ≥ 110 mmHg).
  • New onset seizures (within 3 months prior to Baseline) or poorly controlled seizures.
  • Any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy. Prior treatment with low-dose cytarabine during the past 2 years.
  • Investigational therapy within 4 weeks of Baseline/Day 1 visit.
  • Psychiatric illness or social situation that would limit the patient's ability to tolerate and/or comply with study requirements.

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Rochester, Minn.

Mayo Clinic principal investigator

Aref Al-Kali, M.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

  • Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System. Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts. One patient with a complete bone marrow response also achieved a complete cytogenetic response. A second patient with stable bone marrow blasts achieved a partial cytogenetic response. Two of the responding patients and three patients with stable disease had hematological improvements. Rigosertib-induced bone marrow blast decreases and stability appeared to be predictive of prolonged survival. IV rigosertib had a favorable safety profile without significant myelosuppression. Most common drug-related toxicities included fatigue, diarrhea, nausea, dysuria, and hematuria. In summary, IV rigosertib is well tolerated and has clinical activity in patients with higher risk MDS following DNMT inhibitor treatment. A multinational pivotal phase 3 randomized clinical trial of rigosertib versus best supportive care for patients with MDS with excess blasts following prior treatment with DNMT inhibitors (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE) has recently completed enrollment. Read More on PubMed
  • We previously demonstrated upregulation of c-myc, survivin, and cyclin D1 in CD34+ bone marrow mononuclear cells (BMMNCs) of patients with trisomy 8 and monosomy 7 myelodysplastic syndromes (MDS). "Knockdown" of cyclin D1 by RNA interference decreased trisomy 8 cell growth, suggesting that this might be a therapeutic target in MDS. Read More on PubMed
  • In a Phase I/II clinical trial, 13 higher risk red blood cell-dependent myelodysplastic syndrome (MDS) patients unresponsive to hypomethylating therapy were treated with the multikinase inhibitor ON 01910.Na. Responses occurred in all morphologic, prognostic risk and cytogenetic subgroups, including four patients with marrow complete responses among eight with stable disease, associated with good drug tolerance. In a subset of patients, a novel nanoscale immunoassay showed substantially decreased AKT2 phosphorylation in CD34+ marrow cells from patients responding to therapy but not those who progressed on therapy. These data demonstrate encouraging efficacy and drug tolerance with ON 01910.Na treatment of higher risk MDS patients. Read More on PubMed

Study Results Summary

Not yet available

Supplemental Study Information

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CLS-20111978

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