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

NCT03593915 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: TPI-ALV-102
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 12

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.

Conditions

Myelodysplastic Syndromes (MDS)

Keywords

Previously untreated MDS; MDS who have received <6 cycles of treatment with hypomethylating agents (HMAs); 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; Sumitomo Oncology SMPO; Cancer; Phase 1b/2

Outcome Measures

Primary Outcomes (2)

• Number of Participants With Adverse Events and Serious Adverse Events

  Assessment of safety of alvocidib administered in combination with either decitabine (DEC) or azacitidine (AZA) by reporting of adverse events and serious adverse events

  From the time of first dose to 30 days after the last dose, an average of 33.7 weeks.

• Tolerability of Alvocidib as Evaluated by Incidence of Dose Limiting Toxicities (DLTs) as Observed in Cycle 1

  The DLTs are defined as follows based on the NCI CTCAE v5.0: 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; and ≥Grade 3 creatinine elevation that does not resolve to \<G2 within 7 days.

  Cycle 1 (28 days)

Secondary Outcomes (2)

• Determination of the Complete Response Rate

  From the date of first treatment, every 8 weeks, for the first 6 cycles, for an average of 26 weeks

• Improvement in Transfusion Dependence

  Duration of study treatment up to 6 months

Study Arms (1)

Ph 1b and 2: MDS

EXPERIMENTAL

* Patients with previously untreated MDS * Patients with MDS who have received \<6 cycles of HMAs (during dose escalation only) * 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 (during dose escalation only) or Azacitidine

Interventions

Alvocidib Plus Decitabine (during dose escalation only) or Azacitidine COMBINATION_PRODUCT

PHASE 1b: Decitabine administered as an 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 (hybrid dosing) Once the maximum dose of alvocidib administered via hybrid dosing has been determined, 2 cohorts of patients will receive azacitidine followed by alvocidib administered as an IV infusion. Azacitidine may be administered as either an IV bolus over 10 to 40 minutes or as a subcutaneous (SC) injection on either a 7 day or 5-2 2 schedule. Regardless of which azacitidine schedule or route of administration is used, alvocidib will be given on Day 10 as a 30-to-60 minute IVI PHASE 2: The Phase 2 study will use the RP2D from the Phase 1b study and follow a Simon 2-stage minimax design using the RP2D of alvocidib administered as a 30-to-60 minute IV infusion determined in the Ph1b study to explore efficacy of alvocidib when administered in sequence after azacitidine.

Ph 1b and 2: MDS

Eligibility Criteria

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

You may qualify if:

• Aged ≥18 years
• Phase 1b Dose Escalation: Patients with previously untreated MDS and patients with MDS who received fewer than six (6) cycles of previous HMAs. Phase 1b Expansion: Untreated patients with de novo or secondary MDS. Phase 2: Untreated patients with de novo or secondary MDS
• Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score ≤2 at enrollment
• 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.)
• Patients with a life expectancy of ≥3 months (90 days)
• 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):
• Serum creatinine: ≤1.8× the upper limit of the normal (ULN) range
• Total bilirubin: ≤2× the ULN
• Aspartate transaminase (AST) and alanine transaminase (ALT): ≤3× the ULN
• Left ventricular ejection fraction (LVEF) \>45% by echocardiogram or multigated acquisition (MUGA) scan
• Be able to comply with the requirements of the entire study.
• Patients with Revised International Prognostic Scoring System (IPSS-R) intermediate-, high-, and very high-risk MDS

You may not qualify if:

• Presence of concomitant severe cardiovascular disease:
• Patients who had myocardial infarction within 6 months (180 days) before enrollment
• 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
• Presence of uncontrolled or uncontrollable infection(s); or ≥Grade 3 infection according to NCI CTCAE v5.0
• 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
• Patients with a dry tap on bone marrow aspiration before enrollment
• 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)
• 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)
• Patients with ≥Grade 2 hemorrhage according to NCI CTCAE v5.0
• Patients who have previously received alvocidib or another cyclin-dependent kinase 9 (CDK9) inhibitor
• Patients who are pregnant or breastfeeding
• Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception associated with a low failure rate prior to study entry, for the duration of study participation and for at least 6 months after the last dose of study drug. (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.)
• 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 at least 3 months after the last administration of study treatment.
• Patients who are inappropriate for participation in the study for other reasons in the opinion of the investigator or sub-investigator(s)
• Patients with a known hypersensitivity to decitabine (those patients enrolled in escalation) or azacitidine or mannitol

Sponsors & Collaborators

• Sumitomo Pharma America, Inc.: lead

Study Sites (12)

University of Chicago

Chicago, Illinois, 60637, United States

Location

University of Iowa

Iowa City, Iowa, 52242, United States

Location

Johns Hopkins

Baltimore, Maryland, 21218, United States

Location

Columbia University

New York, New York, 10032, United States

Location

University of North Carolina

Chapel Hill, North Carolina, 27599, United States

Location

US Oncology - Texas Oncology - Austin Midtown

Austin, Texas, 78705, United States

Location

US Oncology - Texas Oncology - Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

US Oncology - Texas Oncology - Fort Worth

Fort Worth, Texas, 76104, United States

Location

US Oncology - Texas Oncology - San Antonio Medical Center

San Antonio, Texas, 78240, United States

Location

US Oncology - Texas Oncology - Tyler

Tyler, Texas, 75702, United States

Location

US Oncology - Virginia Cancer Specialists, PC

Fairfax, Virginia, 22031, United States

Location

US Oncology - Northwest Cancer Specialists, P.C.

Vancouver, Washington, 98684, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Neoplasms

Interventions

alvocidib; Decitabine; Azacitidine

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; 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

Limitations and Caveats

A business decision was made to stop enrollment and the study was discontinued on 17 November 2020. Consistent with Food and Drug Administration and International Council for Harmonisation guidance on the content for abbreviated and synoptic CSRs, only safety data are analyzed and reported.

Results Point of Contact

• Title: Holly Beever
• Organization: Sumitomo Oncology

holly.beever@oncology.sumitomo-pharma.com

210-365-9014

Study Officials

• Stephen Anthony, DO

  Sumitomo Pharma America, Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

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: May 24, 2018
• First Posted: July 20, 2018
• Study Start: August 29, 2018
• Primary Completion: August 16, 2021
• Study Completion: August 16, 2021
• Last Updated: November 9, 2023
• Results First Posted: October 21, 2022

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (12)