Single-Agent Glasdegib In Patients With Myelofibrosis Previously Treated With Ruxolitinib

NCT02226172 | Terminated Phase 2 Results DMC

• 4 other identifiers: B1371013SMOI2014-000933-212014-001048-40
• Study Type: interventional
• Target: 21
• Locations: 2 countries
• Sites: 19

Brief Summary

A lead-in cohort of \~20 patients with primary or secondary myelofibrosis previously treated with 1 or more Janus kinase inhibitors enrolled to single-agent glasdegib to evaluate safety and tolerability. Following the lead-in, a phase 2, double blind, 2-arm study, randomized 2:1 to oral single-agent glasdegib versus placebo in 201 patients resistant or intolerant to ruxolitinib.

Conditions

Primary Myelofibrosis; Post-polycythemia Vera Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis

Keywords

Primary myelofibrosis; Secondary myelofibrosis; PMF; PET-MF; PPV-MF; Ruxolitinib resistant or intolerant; previously treated myelofibrosis; smoothened inhibitor; oral; single agent.

Outcome Measures

Primary Outcomes (7)

• Percentage of Participants Achieving Spleen Volume Reduction (SVR) ≥35% as Measured by Magnetic Resonance Imaging (MRI)/Computed Tomography (CT) Scan at Week 24 in the Randomized Cohort

  The double blind, randomized, placebo controlled phase of the study was not enrolled after the study was terminated early so no data were collected to assess this endpoint.

  Week 24

• Number of Participants With Treatment -Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort

  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.

  Baseline up to Week 131

• Number of Participants With Treatment Emergent Treatment -Related Adverse Events (AEs) and Serious Adverse Events (SAEs): Lead-in Cohort

  Treatment-related AE was any untoward medical occurrence attributed to study drug in a participant who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator. AEs included both serious and non-serious adverse event.

  Baseline up to Week 131

• Number of Participants With Treatment Emergent Adverse Events (AEs) According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03: Lead-in Cohort

  AE was untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. SAE was AE resulting in any outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience; persistent or significant disability; congenital anomaly.Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug (up to Week 131) that were absent before treatment or that worsened relative to pretreatment state.AE were assessed according to maximum severity grading based on NCI CTCAE Version 4.03.Grade 1=mild; Grade 2=moderate; within normal limits. Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening or disabling; urgent intervention indicated; Grade 5=death. Only categories with at least 1 participant with event were reported.

  Baseline up to Week 131

• Number of Participants With Laboratory Abnormalities: Lead-in Cohort

  Abnormality: hematology: hemoglobin less than (\<)0.8\*lower limit of normal(LLN), platelets \<0.5\*LLN greater than (\>)1.75\*upper limit of normal(ULN), white blood cell count(WBC) \<0.6\* LLN \>1.5\* ULN,lymphocytes, total neutrophils\<0.8\* LLN \>1.2\* ULN, band Cells, basophils, eosinophils, monocytes \>1.2\*ULN, blast cells \>1.0\*ULN. Coagulation: activated partial thromboplastin time, prothrombin international ratio \>1.1\* ULN. Liver function: bilirubin \>1.5\*ULN, AST, ALT,lactate dehydrogenase,alkaline phosphatase \>3.0\*ULN, protein,albumin \<0.8\* LLN \>1.2\* ULN. Renal:blood urea nitrogen,creatinine \>1.3\*ULN,uric acid \>1.2\*ULN.Electrolytes: sodium \<0.95\*LLN \>1.05\*ULN, potassium, chloride, calcium, magnesium \<0.9\* LLN \>1.1\*ULN,phosphate \<0.8\* LLN \>1.2\* ULN.Chemistry: glucose \<0.6\*LLN \>1.5\*ULN,creatine kinase \>2.0\*ULN, amylase,lipase \>1.5\*ULN.Urinalysis: protein, blood \>1.0\*ULN,red blood cells,WBC \>=20,epithelial cells \>=6,casts,granular casts,hyaline \>1,cellular casts,crystals\>=1,bacteria \>20.

  Baseline up to Week 131

• Number of Participants With Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and Above Hematological Test Abnormalities: Lead-in Cohort

  Anemia (grade \[g\]1:\< LLN to 10 gram per deciliter \[g/dL\],g2:\<10 to 8g/dL,g3:\<8g/dL, g4:lifethreatening); platelet (g1:\<LLN to 75\*10\^3/millimeter\[mm\]\^3, g2:\<75\*10\^3/mm\^3 to 50\*10\^3/mm\^3, g3:\<50\*10\^3/mm\^3 to 25\*10\^3/mm\^3, g4:\<25\*10\^3/mm\^3); lymphopenia (g1:\<LLN to 8\*10\^2/mm\^3, g2:\<8\*10\^2 to 5\*10\^2/mm\^3, g3:\<5\*10\^2 to 2\*10\^2/mm\^3, g4:\<2\*10\^2/mm\^3);neutrophil (Absolute) (g1:\<LLN to 15\*10\^2/mm\^3, g2:\<15\*10\^2 to 10\*10\^2/mm\^3, g3:\<10\*10\^2 to 5\*10\^2/mm\^3, g4:\<5\*10\^2/mm\^3); white blood cell count(g1:\<LLN to 3\*10\^3/mm\^3, g2:\<3\*10\^3 to 2\*10\^3/mm\^3, g3:\<2\*10\^3 to 1\*10\^3/mm\^3, g4:\<1\*10\^3/mm\^3); hemoglobin (g1:increase in hemoglobin level \>0 to 2 g/dL above ULN or above baseline if baseline is above ULN, g2:increase in hemoglobin level\>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3: increase in hemoglobin level\>4 g/dL above ULN or above baseline if baseline is above ULN).

  Baseline up to Week 131

• Number of Participants With Laboratory Test Abnormalities According to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3 and Above Chemistry Test Abnormalities: Lead-in Cohort

  ALT/AST g1:\>ULN 3\*ULN, g2:\>3-5\*ULN, g3:\>5 20\*ULN, g4:\>20\*ULN); Alkaline Phosphatase (g1:\>ULN 2.5\*ULN,g2:\>2.5-5\*ULN, g3:\>5 20\*ULN, g4:\>20\*ULN); Creatinine (g1:\>ULN-1.5\*ULN,g2:\>1.5-3\*ULN, g3:\>3 6\*ULN, g4:\>6\*ULN);hyperglycemia (g1:\>ULN-160,g2:\>160 250, g3:\>250 500, g4:\>500mg/dL);bilirubin(total) (g1:\>ULN-1.5\*ULN, g2:\>1.5-3\*ULN, g3:\>3 10\*ULN,g4:\>10\*ULN);hypoglycaemia (g1:\<LLN-55,g2:\<55-40, g3:\<40 30,g4:\<30mg/dL); hyperkalemia (g1:\>ULN-5.5,g2:\>5.5-6, g3:\>6 7,g4:\>7mmol/L);hypokalemia (g1:\<LLN-3,g2:\<LLN-3, g3:\<3 2.5, g4:\<2.5mmol/L);hypermagnesemia (g1:\>ULN-3,g3:\>3 8, g4:\>8mg/dL);hypocalcemia (g1:\<LLN-8,g2:\<8-7, g3:\<7-6, g4:\<6mg/dL); hypercalcemia (g1:\>ULN-11.5,g2:\>11.5-12.5, g3:\>12.5-13.5, g4:\>13.5mg/dL); hypomagnesemia (g1:\<LLN-1.2,g2:\<1.2-0.9,g3:\<0.9-0.7, g4:\<0.7mg/dL); hyponatremia (g1:\<LLN-130,g3:\<130-120, g4:\<120mmol/L);hypoalbuminemia (g1:\<LLN-3,g2:\<3 2,g3:\<2, g4:lifethreatening);hypophosphatemia (g1:\<LLN-2.5,g2:\<2.5-2, g3:\<2-1, g4:\<1mg/dL).

  Baseline up to Week 131

Secondary Outcomes (21)

• Percentage of Participants Achieving SVR ≥35% as Measured by Magnetic Resonance Imaging/Computed Tomography Scan at Week 24 in the Lead-in Cohort

  Week 24

• Percentage of Participants Achieving ≥50% Reduction From Baseline in Total Symptom Score (TSS) as Measured by the Myeloproliferative Neoplasm-Symptom Assessment Diary (MPN-SAD) at Week 24 in the Lead-in Cohort

  Week 24

• Monthly Mean Change From Baseline in Overall Total Symptom Score (TSS) in the Lead-in Cohort

  Weeks 12, 24, 36 and 48

• Percentage of Participants Achieving Anemia Response (Transfusion Dependent Versus Independent) in the Lead-in Cohort

  Baseline to end of treatment

• Maximum Observed Glasdegib Plasma Concentration (Cmax), Minimum Glasdegib Plasma Concentration Observed Prior to the Next Dose (Cmin), and Average Observed Glasdegib Plasma Concentration (Cavg) in the Lead-in Cohort

  Cycle 1, Day 15

Study Arms (2)

Arm A

EXPERIMENTAL

Oral daily dose of glasdegib (PF-04449913) 100 mg tablet in a continuous regimen of 28-day cycles.

Drug: Glasdegib (PF-04449913)

Arm B

PLACEBO COMPARATOR

Oral daily dose of placebo 100 mg tablet in a continuous regimen of 28-day cycles.

Drug: Placebo

Interventions

Glasdegib (PF-04449913) DRUG

Oral daily dose of glasdegib (PF-04449913) 100 mg tablet in a continuous regimen of 28-day cycles.

Arm A

Placebo DRUG

Oral daily dose of placebo 100 mg tablet in a continuous regimen of 28-day cycles.

Arm B

Eligibility Criteria

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

You may qualify if:

• Diagnosis of primary MF (PMF) or secondary MF (PET-MF and PPV-MF) as per WHO 2008 criteria.
• Lead-in cohort: resistant or intolerant to 1 or more Janus kinase inhibitors (licensed or experimental).
• Randomized cohort: resistant or intolerant to prior ruxolitinib therapy. Documentation by the Investigator that the patient has exhausted available treatment options (eg, resistant or intolerant to hydroxyurea, etc).
• Spleen 5 cm below the inferior left costal margin as measured by manual palpation.
• Active symptomatic MF as defined by the screening MPN-SAD patient-reported instrument requiring a severity score of at least 5 on one symptom, or a severity score of ≥ 3 on at least two of the symptoms (on a 0 to 10 scale).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2, or 3.
• Adequate organ function, demonstrated by the following laboratory values:
• Absolute Neutrophil Count 75 x 10(9)/L;
• Platelet count \>50 x 10(9)/L with no evidence of bleeding and not requiring platelet transfusions;
• Serum creatinine \<1.5 x upper limit of normal (ULN) or estimated creatinine clearance 60 mL/min (as calculated using the standard method of the institution);
• Serum amylase or lipase \<1.5 x ULN;
• Aspartate aminotransferase and alanine aminotransferase values 3.0 x ULN (or 5x ULN in the case of patients with MF accompanied by hepatic extramedullary hematopoiesis, as manifested by any degree of hepatomegaly).
• Total bilirubin values \<1.5 x ULN unless the bilirubin is principally unconjugated (in the context of hemolysis) or there is documented Gilbert's disease.
• Serum electrolyte values \< Grade 2 (sodium, potassium, calcium, phosphorous and magnesium), per CTCAE v.4.03.
• Recovery to Grade 1 from all clinically significant adverse events related to prior MF therapy, including transplant-related toxicities.

You may not qualify if:

• Prior treatment with a licensed or experimental smoothened inhibitor.
• Randomized cohort only: Prior treatment with a Janus kinase inhibitor other than ruxolitinib.
• Other anti-cancer therapy up to 14 days prior to enrollment, with the exception of hydroxyurea, which can be given up to 4 days prior to enrollment.
• Splenic irradiation 3 months prior to enrollment.
• History of congenital long QT syndrome, or a baseline \>470 msec QTcF abnormality (average of the triplicate reading).
• Evidence of significant cardiac disease, for example: symptomatic cardiac heart failure (CHF, NYHA class 3), complete bundle branch block, significant atrial or ventricular tachyarrhythmias and any unstable cardiac arrhythmias requiring medication.
• History of myocardial infarction or unstable angina within 6 months prior to enrollment.
• Uncontrolled inflammatory bowel disease, peptic ulcer disease or history of significant gastro intestinal bleeding within 6 months of enrollment.
• Any condition requiring chronic use of moderate/high dose steroids (equivalent to 10 mg QD prednisone).
• Hematopoietic growth factor receptor agonists (eg, erythropoietin (Epo), granulocyte colony stimulating factor, romiplostim, eltrombopag within 28 days of enrollment.
• Currently active malignancy (other than MF). Prior malignancies are allowed so long as there is no evidence of disease recurrence within the last 2 years (with the exception of fully excised, non-complicated basal cell carcinoma which can have been active within the prior 2 years, and certain localized, non-invasive fully excised skin, cervical, breast, prostate or bladder tumors).
• Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, non-alcoholic steatohepatitis \[NASH\]).
• Active, uncontrolled bacterial, fungal or viral infection, including hepatitis B, hepatitis C, known human immunodeficiency virus or acquired immunodeficiency syndrome related illness.
• Active graft versus host disease (GVHD) with other than grade 1 skin involvement or GVHD requiring immunosuppressive treatment.
• Uncontrolled disseminated intravascular coagulation.

Sponsors & Collaborators

• Pfizer: lead

Study Sites (19)

Mayo Clinic Building - Phoenix

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic Hospital

Phoenix, Arizona, 85054, United States

Location

Mayo Clinic

Scottsdale, Arizona, 85259, United States

Location

UC San Diego Moores Cancer Center - Investigational Drug Services

La Jolla, California, 92037-0845, United States

Location

UCSD Medical Center Clinical Laboratory - La Jolla

La Jolla, California, 92037, United States

Location

University of California San Diego (UCSD) Moores Cancer Center

La Jolla, California, 92093-0698, United States

Location

UC San Diego Medical Center- Hillcrest

San Diego, California, 92103, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Weill Cornell Medical College - New York-Presbyterian Hospital

New York, New York, 10021, United States

Location

Herbert Irving Comprehensive Cancer Center-Columbia University Medical Center

New York, New York, 10032, United States

Location

Weill Cornell Medical College-New York Presbyterian Hospital

New York, New York, 10065, United States

Location

Cleveland Clinic - Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

Huntsman Cancer Institute-University of Utah

Salt Lake City, Utah, 84112, United States

Location

University of Utah, Huntsman Cancer Hospital

Salt Lake City, Utah, 84112, United States

Location

Froedtert Hospital and Medical College of Wisconsin

Milwaukee, Wisconsin, 53226-3522, United States

Location

Kobe University Hospital

Kobe, Hyōgo, 6500017, Japan

Location

Osaka University Hopsital

Suita-Shi, Osaka, 565-0871, Japan

Location

Juntendo University Hospital

Bunkyo-ku, Tokyo, 113-8431, Japan

Location

Tokyo Medical University Hospital

Tokyo, 160-0023, Japan

Location

Related Links

• To obtain contact information for a study center near you, click here.

MeSH Terms

Conditions

Primary Myelofibrosis

Interventions

glasdegib

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Pfizer ClinicalTrials.gov Call Center
• Organization: Pfizer, Inc.

ClinicalTrials.gov_Inquiries@pfizer.com

1-800-718-1021

Study Officials

• Pfizer CT.gov Call Center

  Pfizer

  STUDY DIRECTOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2014
• First Posted: August 27, 2014
• Study Start: October 6, 2014
• Primary Completion: December 14, 2016
• Study Completion: January 31, 2018
• Last Updated: January 17, 2019
• Results First Posted: April 2, 2018

Record last verified: 2018-12

Locations

US (15); JP (4)