Safety and Efficacy Study of CYT387 in Primary Myelofibrosis (PMF) or Post-polycythemia Vera (PV) or Post-essential Thrombocythemia (ET)

NCT00935987 | Completed Phase 1

• 1 other identifier: CCL09101
• Study Type: interventional
• Target: 166
• Locations: 3 countries
• Sites: 6

Brief Summary

This study seeks to (i) determine a safe and tolerated dose of CYT387 (momelotinib) given to patients with PMF, post-PV or post-ET and, (ii) assess the effectiveness of orally-administered CYT387 as a treatment for PMF, post-PV or post-ET.

Conditions

Primary Myelofibrosis; Post-Polycythemia Vera Myelofibrosis; Post-Essential Thrombocythemia Myelofibrosis

Keywords

Primary Myelofibrosis; Post-Polycythemia Vera; Post-Essential Thrombocythemia; CYT387

Outcome Measures

Primary Outcomes (3)

• Safety and tolerability, dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of orally-administered CYT387 in patients with PMF or post-ET/PV MF.

  Ongoing throughout therapy up until 30 days after last dose of CYT387

• Objective Response Rate (ORR), as measured by complete response (CR) rate, partial response (PR) rate and clinical improvement (CI) rate according to International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) consensus criteria

  The Objective Response Rate (ORR), as measured by complete response (CR) rate, partial response (PR) rate and clinical improvement (CI) rate according to International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) is to be measured at the end of every cycle of therapy.

  Baseline to study completion

• Pharmacokinetics of CYT387 in patients with PMF or post-ET/PV MF

  The pharmacokinetics (PK) of CYT387 in patients with PMF or post-ET/PV MF is to be assessed on Day 1 and Day 28 in Cycle 1 of therapy

  Baseline to end of Cycle 1

Secondary Outcomes (5)

• Effect of CYT387 on bone marrow or peripheral blood cytogenetic findings in patients with PMF or post-ET/PV MF.

  Baseline to study completion

• Effect of CYT387 on peripheral blood granulocyte JAK2V617F allele burden in patients with PMF or post-ET/PV MF.

  Baseline to study completion

• Effect of CYT387 on peripheral blood endogenous myeloid colony formation in patients with PMF or post-ET/PV MF.

  Baseline to study completion

• Effect of CYT387 on plasma levels of inflammatory, fibrogenic and angiogenic cytokines in patients with PMF or post-ET/PV MF

  Baseline to study completion

• Pharmacodynamic correlates of CYT387 activity in patients with PMF or post-ET/PV MF who are receiving treatment with CYT387.

  Baseline to Cycle 9

Study Arms (1)

CYT387

EXPERIMENTAL

Drug: CYT387

Interventions

CYT387 DRUG

For the Part 1 dose-escalation portion of the study, patients will be assigned to dose levels in successive cohorts starting with a dose in the first cohort of 100 mg/day. CYT387 will be orally self-administered as a single daily dose beginning on Day 1 of the study, and thereafter at approximately the same time each day of the 28-day cycle. It is recommended that all doses be preceded by a 2-hour fast from food and beverages, and be followed by a 1-hour post-dose fast from food and beverages. Twenty additional patients will be assigned to a 150 mg BID (twice daily) dosing schedule. CYT387 will be orally self-administered twice-daily with doses approximately 10-12 hours apart beginning on Day 1 of the study, and thereafter at approximately the same times each day of the 28-day cycle. For the Part 2 dose confirmation portion of the study, patients will be assigned to either 150 mg or 300 mg QD (once daily) dose groups.

Also known as: Momelotinib

CYT387

Eligibility Criteria

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

You may qualify if:

• Diagnosis of PMF or post-polycythemia Vera (PV) or post-essential Thrombocythemia (ET) MF as per revised World Health Organization (WHO) criteria.
• High-risk or Intermediate-2 risk MF (as defined by the International Prognostic Scoring System \[IPSS\]; Appendix 13.6); or intermediate-I risk MF (IPSS) associated with symptomatic splenomegaly/hepatomegaly and/or unresponsive to available therapy.
• Must be at least 18 years of age with life expectancy of ≥ 12 weeks.
• Must be able to provide informed consent and be willing to sign an informed consent form.
• Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.
• Must have evidence of acceptable organ function within 7 days of initiating study drug as evidenced by the following:
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN) (or ≤ 5 x ULN if in the investigator's opinion the elevation is due to extramedullary hematopoiesis)
• Bilirubin ≤ 2.0 x ULN or direct bilirubin \< 1.0
• Serum creatinine ≤ 2.5 x ULN
• Absolute neutrophil count ≥ 500/µL
• Platelet count ≥ 50,000/µL
• Females of childbearing potential must have a negative pregnancy test within 4 days of initiating study drug.

You may not qualify if:

• Any chemotherapy (eg, hydroxyurea), immunomodulatory drug therapy (eg, thalidomide), immunosuppressive therapy, corticosteroids \> 10 mg/day prednisone or equivalent, or growth factor treatment (eg, erythropoietin) within 14 days prior to initiation of study drug.
• Incomplete recovery from major surgery within four weeks of study entry.
• Radiation therapy within four weeks of study entry.
• Women of childbearing potential, unless surgically sterile for at least 3 months (ie, hysterectomy), OR postmenopausal for at least 12 months (FSH \> 30 U/mL), OR unless they agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through end of study. Permitted methods for preventing pregnancy must be communicated to study subjects and their understanding confirmed.
• Men who partner with a woman of childbearing potential, unless they agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through to the end of study. Permitted methods for preventing pregnancy must be communicated to study subjects and their understanding confirmed.
• Females who are pregnant or are currently breastfeeding.
• Known positive status for HIV.
• Clinically active hepatitis B or C.
• Diagnosis of another malignancy unless free of disease for at least three years following therapy with curative intent. Patients with early-stage basal cell or squamous cell skin cancer, cervical intraepithelial neoplasia, cervical carcinoma in situ or superficial bladder cancer may be eligible to participate at the Investigator's discretion.
• Any acute active infection.
• Cardiac dysrhythmias requiring treatment, or prolongation of the QTc (Fridericia) interval to \> 450 msec for males or \> 470 msec for females at prestudy screening, unless attributable to pre-existing bundle branch block.
• Presence of ≥ Grade 2 peripheral neuropathy.
• Uncontrolled congestive heart failure (New York Heart Association Classification 3 or 4), uncontrolled or unstable angina, myocardial infarction, cerebrovascular accident, or pulmonary embolism within 3 months prior to initiation of study drug.
• Uncontrolled inter current illness or any concurrent condition that, in the Investigator's opinion, would jeopardize the safety of the patient or compliance with the protocol.

Sponsors & Collaborators

• Sierra Oncology LLC - a GSK company: lead

Study Sites (6)

Stanford Cancer Center

Stanford, California, 94305-5821, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

The Royal Melbourne Hospital

Parkville, Victoria, 3050, Australia

Location

Princess Margaret Hospital

Toronto, Ontario, M5G 2M9, Canada

Location

Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Related Publications (1)

• Tefferi A, Barraco D, Lasho TL, Shah S, Begna KH, Al-Kali A, Hogan WJ, Litzow MR, Hanson CA, Ketterling RP, Gangat N, Pardanani A. Momelotinib therapy for myelofibrosis: a 7-year follow-up. Blood Cancer J. 2018 Mar 7;8(3):29. doi: 10.1038/s41408-018-0067-6.

  PMID: 29515114 DERIVED

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

N-(cyanomethyl)-4-(2-((4-(4-morpholinyl)phenyl)amino)-4-pyrimidinyl)benzamide

Condition Hierarchy (Ancestors)

Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Study Officials

• Ayalew Tefferi, MD

  Mayo Clinic

  STUDY CHAIR

• Andrew Roberts, MD

  Melbourne Health

  PRINCIPAL INVESTIGATOR

• Jason Gotlib, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

• Vikas Gupta, MD

  Princess Margaret Hospital, Canada

  PRINCIPAL INVESTIGATOR

• Shireen Sirhan, MD

  Jewish General Hospital

  PRINCIPAL INVESTIGATOR

• Animesh Pardanani, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

• Martha Wadleigh, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

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: July 7, 2009
• First Posted: July 9, 2009
• Study Start: November 1, 2009
• Primary Completion: April 1, 2012
• Study Completion: April 1, 2012
• Last Updated: February 1, 2019

Record last verified: 2019-01

Locations

AU (1); CA (2); US (3)