Phase II Hedgehog Inhibitor for Myelodysplastic Syndrome (MDS)

NCT01842646 | Completed Phase 2 Results

• 1 other identifier: MCC-17302
• Study Type: interventional
• Target: 35
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being done to see how safe an investigational drug is and test how well it will work to help people with refractory/relapsed myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML).

Conditions

Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML)

Keywords

Leukemia; Myeloid Malignancies

Outcome Measures

Primary Outcomes (1)

• Overall International Working Group (IWG) 2006 Response Rate

  Response recorded from the start of the treatment until disease progression/recurrence. All responses must last for at least 8 weeks. Complete Remission (CR): Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines, Persistent dysplasia will be noted, Peripheral blood: Hemoglobin ≥ 11 g/dL, Platelets ≥ 100 x 10\^9/L, Neutrophils ≥ 1.0 x 10\^9/L, Blasts 0% ; Partial Remission (PR): All CR criteria if abnormal before treatment, except: Bone marrow blasts decreased by ≥ 50% over pretreatment but still \> 5%, Cellularity and morphology not relevant; Marrow CR or Hematological Improvement (HI): Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment Peripheral blood: if HI responses, they will be noted in addition to marrow CR. Further investigation of PF-04449913 would not be warranted if it produced an overall response rate (CR + PR + marrow CR+HI) of 10% or less (p0), and would be warranted if it produced an overall response rate of 30% or more (p1).

  Up to 2 years, 4 months

Secondary Outcomes (4)

• Median Overall Survival (OS)

  Up to 2 years, 4 months

• Median Event Free Survival

  Up to 2 years, 4 months

• Median Time to Transformation to Acute Myeloid Leukemia (AML)

  Up to 2 years, 4 months

• Number of Participants With Treatment Emergent Adverse Events

  2 years, 4 months

Study Arms (1)

PF-04449913 Treatment

EXPERIMENTAL

Treatment will be administered on an outpatient basis. All patients will be treated with an oral dose PF-04449913 at 100 mg daily in 4-week cycles for a total of 4 cycles. Patients who demonstrate no evidence of progressive disease (i.e. stable disease or better) may continue on treatment until disease progression or loss of response, limiting toxicity, or death.

Drug: PF-04449913

Interventions

PF-04449913 DRUG

Patients will be enrolled according to a two-step study design. Twenty patients will be enrolled in the first stage. All patients will be given a daily oral dose of PF-0444913 100 mg for up to 4 cycles, with an optional continuation phase. Dose escalation to 200 mg will be provided for patients who do not have at least hematologic improvement following 2 cycles, and dose reduction to 50 mg will be permitted for patients with significant toxicity. If at least 2 patients respond in the initial stage, and additional 15 patients will be enrolled in the second stage.

Also known as: Oral Hedgehog Inhibitor, Smoothened (SMO) Inhibitor

PF-04449913 Treatment

Eligibility Criteria

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

You may qualify if:

• Must have a pathologically confirmed diagnosis by World Health Organization (WHO) Criteria of MDS, CMML, or acute myeloid leukemia (AML) (except acute promyelocytic leukemia) with \< 30% bone marrow blasts (RAEB-t by French American British criteria)
• Hypomethylating agent (azacitidine and/or decitabine) failure, defined as lack of response, disease progression, loss of response, or intolerance as deemed by the study investigator
• Adequate renal function, as evidenced by a serum creatinine ≤ 2 times the institutional upper limit of normal
• Adequate hepatic function, as evidenced by a serum bilirubin \< 2 times the institutional upper limit of normal and an aspartic transaminase (AST) and alanine transaminase (ALT) \< 2 times the institutional upper limit of normal. Indirect hyperbilirubinemia due to Gilbert's disease or hemolysis is permitted.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• Ability to understand and the willingness to sign a written informed consent document

You may not qualify if:

• Patients with a history of prior therapy with another investigational agent within 4 weeks of the first planned dose of PF-0444913
• Patients may not be receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to PF-04449913
• Prior therapy with another hedgehog inhibitor
• Concurrent use of any other agent for MDS, CMML, or AML. Growth factor use with epoetin, darbepoetin, or granulocyte colony-stimulating factor must be terminated at least 2 weeks before initiation of study treatment.
• Any uncontrolled concurrent illness that would, in the opinion of the investigator, limit compliance with study requirements
• Second malignancy requiring active therapy
• A prolonged corrected QT interval (QTc) of ≥480 ms interval on electrocardiogram
• History of metastatic cancer diagnosed less than 2 years prior to the first planned dose of PF-0444913
• Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because PF-04449913 is smoothened inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PF-04449913. Breastfeeding should be discontinued if the mother is treated with PF-04449913.
• Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy. Therefore, HIV-positive patients receiving combination antiretroviral therapy are excluded from the study because of possible pharmacokinetic interactions with PF-04449913.

Sponsors & Collaborators

• H. Lee Moffitt Cancer Center and Research Institute: lead
• Pfizer: collaborator

Study Sites (1)

H. Lee Moffitt Cancer Center and Research Institute

Tampa, Florida, 33612, United States

Location

MeSH Terms

Conditions

Myelodysplastic Syndromes; Leukemia, Myelomonocytic, Chronic; Leukemia

Interventions

glasdegib; SMO protein, human

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Myelodysplastic-Myeloproliferative Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Jeffrey Lancet
• Organization: H. Lee Moffitt Cancer Center and Research Institute

jeffrey.lancet@moffitt.org

813-745-1387

Study Officials

• Jeffrey Lancet, M.D.

  H. Lee Moffitt Cancer Center and Research Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 25, 2013
• First Posted: April 29, 2013
• Study Start: August 29, 2013
• Primary Completion: January 31, 2016
• Study Completion: June 10, 2021
• Last Updated: June 14, 2021
• Results First Posted: March 14, 2017

Record last verified: 2021-06

Locations

US (1)