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A Phase 1b/2 Study of Alvocidib Plus Decitabine in Patients With MDS

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ClinicalTrials.gov Identifier: NCT03593915
Recruitment Status : Recruiting
First Posted : July 20, 2018
Last Update Posted : November 12, 2018
Sponsor:
Information provided by (Responsible Party):
Tolero Pharmaceuticals, Inc.

Brief Summary:

Alvocidib, a cyclin-dependent kinase 9 (CDK 9) inhibitor, in time-sequential therapy demonstrated significant clinical activity in secondary AML patients with prior MDS. Patients with IPSS-R intermediate and above MDS have an increased risk of developing AML and may be treated with the same chemotherapy regimens used in patients with AML. Eight Phase I or II clinical trials have been completed in patients with AML, totaling more than 400 patients with both relapsed/refractory or newly diagnosed AML.

Preclinical studies have demonstrated that decitabine exposure increased the expression of NOXA, which is a specific antagonist of the survival factor MCL 1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well as upregulation of the MCL-1 antagonist, NOXA, following decitabine exposure may result in enhanced antileukemic activity in MCL-1-dependent malignancies.


Condition or disease Intervention/treatment Phase
Myelodysplastic Syndromes (MDS) Combination Product: Alvocidib Plus Decitabine Phase 1 Phase 2

Detailed Description:

PHASE 1b:

Patients will be enrolled in cohorts of 3-6 patients. Escalation of the alvocidib dose will follow a standard 3+3 design with sequential cohorts of 3 patients treated with incrementally higher doses of alvocidib until a dose-limiting toxicity (DLT) is observed and the MTD is established.

Once the MTD or preliminary RP2D is identified, the study will progress to Phase 2.

PHASE 2:

Phase 2 design is based on the Simon 2-stage minimax design (Simon 1989).

  • Stage 1: Up to 15 evaluable patients will be enrolled and treated at the RP2D identified in the Phase 1b study.
  • Stage 2: Ten patients will be enrolled to bring the total enrollment in Phase 2 (including Stage-1 patients) to 25 evaluable patients. Stage-2 patients will also receive the RP2D dose identified in the Phase 1b study. If 6 or more responses are observed in 25 patients, the conclusion will be that the combination regimen is worthy of further investigation.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 49 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2, Open-label Clinical Study to Determine Preliminary Safety and Efficacy of Alvocidib When Administered in Sequence After Decitabine in Patients With MDS
Actual Study Start Date : August 29, 2018
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : May 2022


Arm Intervention/treatment
Experimental: Ph 1b and 2: Pts w/ previously untreated MDS
  • Patients with previously untreated MDS
  • Patients with MDS who have received <6 cycles of HMAs
  • Patients with de novo (cause unknown) or secondary MDS (treatment-related) who are not eligible for intensive induction chemotherapy or stem cell transplant

    • All French-American-British (FAB) subtypes
    • Intermediate and above per IPSS-R groups
Combination Product: Alvocidib Plus Decitabine

PHASE 1b:

Decitabine administered as a 1-hour intravenous (IV) infusion daily for 5 days at a dose of 20 mg/m2 followed on Day 8 by alvocidib as a loading dose over 30 minutes followed by a 4-hour IV infusion

PHASE 2:

The Phase 2 study will use the RP2D from the Phase 1b study and follow a Simon 2-stage minimax design





Primary Outcome Measures :
  1. PHASE 1b: Incidence of dose-limiting toxicities (DLTs) and treatment emergent adverse events. [ Time Frame: 28 days ]

    DLTs as observed in Cy 1. Must be at least possibly related to alvocidib. Any Gr 4 nonhematologic toxicity. Gr 3 nonhematologic toxicity that does not resolve to ≤Gr 2 in 48 hours. Gr 3 diarrhea, mucositis, nausea, or vomiting will be considered dose limiting only if resolution to ≤Gr 2 requires >7 days. ≥Grade 3 neurotoxicity of any duration

    ≥Grade 3 creatinine elevation of any duration Anorexia, fever, neutropenic fever, and infections of any grade Myelosuppression will not be considered in evaluating DLTs in patients except where bone marrow hypoplasia occurs for >50 days with bone marrow (BM) cellularity ≤5% and no evidence of MDS/leukemia.


  2. PHASE 2: Objective response rate using revised International Working Group (IWG) criteria (2006) [ Time Frame: 3 months ]
    Baseline disease assessment performed at screening and subsequent response assessments


Secondary Outcome Measures :
  1. PHASE 1b: Complete Response Rate (CRR: CRR: complete response [CR] / complete response with incomplete blood count recovery [CRi] / CRmarrow / partial response [PR] / hematologic improvement [HI]) [ Time Frame: 3 months ]
    Baseline disease assessment performed at screening and subsequent response assessments

  2. PHASE 1b and 2: Decitabine treatment effect on BH3 profiling results in peripheral blood to find the correlation between the rate of CR/CRi/CRmarrow/PR/HI and BH3 profiling by flow cytometry with an emphasis on MCL-1 dependence. [ Time Frame: 3 months ]
    Assessment of BH3 profiling in peripheral blood



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Aged ≥18 years
  2. Phase 1b: Patients with previously untreated MDS and patients who received fewer than six (6) cycles of previous HMAs Phase 2: Untreated patients with de novo or secondary MDS
  3. Patients with a suspected (eg, persistent unexplained cytopenia, circulating peripheral blasts, etc) MDS and undergoing diagnostic work-up with planned bone marrow assessments, or diagnosed with de novo or therapy-related MDS within 6 months of enrollment (per the 2016 World Health Organization (WHO) guidelines) and undergoing clinical evaluation and planned bone marrow assessments to confirm MDS or to evaluate disease status
  4. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score ≤2 at enrollment
  5. Patients of reproductive potential should use adequate birth control measures, as defined by investigator, during the study treatment period and for at least 60-90 days after the last study treatment.
  6. Provide written informed consent prior to any study-related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.)
  7. Patients with a life expectancy of ≥3 months (90 days)
  8. Patients with adequate major organ functions meeting the following criteria on the basis of laboratory data within 4 weeks (28 days) before enrollment (if multiple data are available, most recent data during the period):

    1. Serum creatinine: ≤1.8× the upper limit of the normal (ULN) range
    2. Total bilirubin: ≤2× the ULN
    3. Aspartate transaminase (AST) and alanine transaminase (ALT): ≤3× the ULN
    4. Left ventricular ejection fraction (LVEF) >45% by echocardiogram or multigated acquisition (MUGA) scan
  9. Be able to comply with the requirements of the entire study.

Exclusion Criteria:

  1. Presence of concomitant severe cardiovascular disease:

    1. Patients who had myocardial infarction within 6 months (180 days) before enrollment
    2. Patients with significant diseases at enrollment that may affect study treatment, such as New York Heart Association (NYHA) Functional Class III or IV heart disease, National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade ≥3 arrhythmia, angina pectoris, abnormal electrocardiogram findings, interstitial pneumonia or pulmonary fibrosis
  2. Presence of concomitant malignancy requiring chemotherapy or any malignancy (except basal and squamous cell carcinoma of the skin) for which the patient received chemotherapy within 6 months prior to enrollment. NOTE: Diagnosis of any previous or concomitant malignancy is thus not an exclusion criterion.
  3. Presence of uncontrolled or uncontrollable infection(s); or ≥Grade 3 infection according to NCI CTCAE v5.0
  4. Presence of any psychological, familial, sociological or geographical condition that, in the opinion of the investigator, could potentially hinder compliance with the study protocol and follow-up schedule
  5. Patients with a dry tap on bone marrow aspiration before enrollment
  6. Patients with concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease, or patients who require long-term systemic steroid therapy greater than the equivalent of 20 mg of prednisone daily (excluding therapy given on an 'as needed' [PRN] basis)
  7. Patients with other documented malignancies within past year aside from synchronous or metachronous multiple cancers with a disease-free period of ≤5 years (excluding carcinoma in situ, mucosal carcinoma, or other such carcinomas curatively treated with local therapy)
  8. Patients with ≥Grade 2 hemorrhage according to NCI CTCAE v5.0
  9. Patients who have previously received alvocidib or another cyclin-dependent kinase 9 (CDK9) inhibitor
  10. Patients who are pregnant or breastfeeding
  11. Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception during the trial and for 90 days (~3 months) after the last administration of study treatment (Patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy, or bilateral tubal ligation / salphingectomy, or postmenopausal for at least 2 years.)
  12. Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second effective method of contraception during the trial and for 60 days after the last administration of study treatment.
  13. Patients who are inappropriate for participation in the study for other reasons in the opinion of the investigator or sub-investigator(s)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03593915


Contacts
Contact: Nissa Ashenbramer, BBA 210-931-2533 nashenbramer@toleropharma.com
Contact: Susan Smith, MSN 210-414-7702 su.smith@toleropharma.com

Locations
United States, Maryland
Johns Hopkins Not yet recruiting
Baltimore, Maryland, United States, 21218
Contact: Amy DeZern, MD         
Principal Investigator: Amy DeZern, MD         
United States, Texas
US Oncology - Texas Oncology - Austin Midtown Recruiting
Austin, Texas, United States, 78705
Contact: Jason Melear, MD    512-421-4163      
Principal Investigator: Jason Melear, MD         
US Oncology - Texas Oncology - San Antonio Medical Center Recruiting
San Antonio, Texas, United States, 78240
Contact: Roger Lyons, MD         
Principal Investigator: Roger Lyons, MD         
US Oncology - Texas Oncology - Tyler Recruiting
Tyler, Texas, United States, 75702
Contact: Habte Yimer, MD    903-579-9800      
Principal Investigator: Habte Yimer, MD         
United States, Washington
US Oncology - Northwest Cancer Specialists, P.C. Recruiting
Vancouver, Washington, United States, 98684
Contact: David A Smith, MD         
Principal Investigator: David A Smith, MD         
Sponsors and Collaborators
Tolero Pharmaceuticals, Inc.
Investigators
Study Director: Stephen Anthony, DO Tolero Pharmaceuticals

Responsible Party: Tolero Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03593915     History of Changes
Other Study ID Numbers: TPI-ALV-102
First Posted: July 20, 2018    Key Record Dates
Last Update Posted: November 12, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Tolero Pharmaceuticals, Inc.:
Patients with previously untreated MDS
Patients with MDS who have received <6 cycles of treatment with hypomethylating agents (HMAs)
Patients with de novo or secondary MDS (treatment-related) who are not eligible for intensive induction chemotherapy or stem cell transplant
FAB subtypes: refractory anemia [RA], RA w/ ringed sideroblasts, RA w/ excess blasts, RA w/ excess blasts in transformation or chronic myelomonocytic leukemia
Intermediate and above per the Revised International Prognostic Scoring System (IPSS-R) groups
Tolero
Cancer
Phase 1b/2

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Decitabine
Azacitidine
Alvocidib
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Growth Inhibitors
Growth Substances
Physiological Effects of Drugs
Protein Kinase Inhibitors