Trial of Pimasertib in Hematological Malignancies

This study has been terminated.
(The trial has been terminated due to an estimated low probability of clinical benefit based on limited anti-leukemic effects observed in safety run-in (Part 1).)
Sponsor:
Information provided by (Responsible Party):
EMD Serono
ClinicalTrials.gov Identifier:
NCT00957580
First received: August 11, 2009
Last updated: February 7, 2014
Last verified: February 2014
  Purpose

This is an open-label, multi-center, dose-escalation trial of pimasertib in blood and bone marrow cancers. The trial will be conducted in two parts:

Part 1 (safety run-in period): Will determine the maximum tolerated dose (MTD) of the study drug in subjects with advanced hematological malignancies.

Part 2: Will assess the anti-leukemic activity of the study drug in older subjects with newly diagnosed poor prognosis Acute Myeloid Leukemia (AML) who are not candidates for intensive chemotherapy.


Condition Intervention Phase
Leukemia, Myeloid, Acute
Hematologic Neoplasms
Drug: Pimasertib
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase II Trial With Safety-Run-In of MEK Inhibitor MSC1936369B in Subjects With Poor Prognosis Acute Myeloid Leukemia and Other Hematological Malignancies

Resource links provided by NLM:


Further study details as provided by EMD Serono:

Primary Outcome Measures:
  • Part 1: Number of subjects with Dose Limiting Toxicities (DLTs) [ Time Frame: Up to Day 29 of Cycle 1 ] [ Designated as safety issue: Yes ]
  • Part 2: Percentage of Subjects with Best Overall Response [ Time Frame: Day 29 of every 29-day cycle until progression reported between day of first patient randomized, September 2009, until cut-off date, December 2012 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Part 1: Number of Subjects with Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  • Part 1: Maximum Concentration (Cmax) of Pimasertib [ Time Frame: Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 2 and 3 ] [ Designated as safety issue: No ]
  • Part 1: Time to Reach Maximum Concentration (tmax) and Apparent Terminal Half-Life (t1/2) of Pimasertib [ Time Frame: Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 2 and 3 ] [ Designated as safety issue: No ]
  • Part 1: Area Under Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above Lower Limit of Quantification (AUC0-t) and Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib [ Time Frame: Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 2 and 3 ] [ Designated as safety issue: No ]
  • Part 1: Apparent Oral Clearance (CL/f) of Pimasertib [ Time Frame: Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 2 and 3 for Regimen 2 and 3 ] [ Designated as safety issue: No ]
  • Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib [ Time Frame: Days 1, 3-5, 8, 19, 26, and 29 in Cycle 1 and Day 1 in Cycle 1 and 2 for Regimen 1 and Days 1, 3-5, 8, 19-21, and 29 in Cycle 1 and Day 1 in Cycle 1 and 2 for Regimen 2 and 3 ] [ Designated as safety issue: No ]
  • Part 1: Percentage of Subjects with Best Overall Response [ Time Frame: Day 29 of every alternate 29-day cycle until progression reported between day of first patient randomized, September 2009, until cut-off date, December 2012 ] [ Designated as safety issue: No ]
  • Part 2: Number of Subjects with TEAEs, Serious TEAEs, and TEAEs Leading to Permanent Treatment Discontinuation [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]

Enrollment: 80
Study Start Date: September 2009
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Regimen 1 (Part 1) Drug: Pimasertib
Pimasertib will be administered orally on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The starting dose will be 8 mg twice daily. The dose escalation will proceed until Maximum Tolerated Dose (MTD) is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Name: MSC1936369B
Experimental: Regimen 2 (Part 1) Drug: Pimasertib
Pimasertib will be administered orally on Days 1 to 21 of a 28-day cycle. The starting dose will be 8 mg twice daily. The dose escalation will proceed until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Name: MSC1936369B
Experimental: Regimen 3 (Part 1) Drug: Pimasertib
Pimasertib will be administered orally on Days 1-28 of a 28-day cycle. The starting dose will be 8 mg twice daily. The dose escalation will proceed until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Name: MSC1936369B
Experimental: Regimen 1 (Part 2) Drug: Pimasertib
Pimasertib will be administered orally twice daily on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. Dose will be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Name: MSC1936369B
Experimental: Regimen 2 (Part 2) Drug: Pimasertib
Pimasertib will be administered orally twice daily on Days 1 to 21 of a 28-day cycle. Dose will be determined by Part 1 of the trial (could be the MTD or lower dose level). The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.
Other Name: MSC1936369B

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

Part 1:

  1. Subjects with one of the following conditions:

    • Primary or secondary AML, pathologically confirmed according to World Health Organization (WHO) classification who meet at least one of the following conditions:

      1. Subjects with second or subsequent relapse after standard therapy, for whom no established treatment options are available
      2. Subjects refractory to available therapies, for example, who failed to achieve complete response (CR) after 2 induction chemotherapy treatments
      3. Newly-diagnosed older subjects (greater than or equal to 75 years of age), not candidates for intensive chemotherapy
    • Subjects with myelodysplastic syndrome (MDS), International Prognostic Scoring System (IPSS) Int-2 or high risk who are resistant or intolerant to standard treatment and not candidates for transplantation
    • Subjects with relapsed or refractory multiple myeloma (MM), who have failed or are intolerant to at least two prior therapies including thalidomide, lenalidomide and bortezomib
    • Subjects with advanced myeloproliferative disorders (MPD) for whom no established treatment options are available
    • Subjects with acute lymphocytic leukemia (ALL), relapsed, refractory or intolerant to standard treatment and for whom no effective treatment options are available
  2. Age greater than or equal to 18 years
  3. Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments
  4. Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Subjects must therefore be willing to use adequate contraception as approved by the Investigator, two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. The use of hormonal contraceptives should be avoided due to a possible drug-drug interaction in female subjects of childbearing age

Part 2:

  1. Subjects (male and female) with newly diagnosed primary or secondary AML pathologically confirmed according to WHO classification who have not been exposed to any prior therapy for AML with the exception of:

    • Emergency leukapheresis and
    • Emergency treatment for hyperleukocytosis with hydroxyurea that is allowed until 24 hours before the start of the trial treatment. Prior therapy for pre-existing hematological conditions, for example, MDS or MPD, including but not limited to hypomethylating agents, is also allowed until at least 2 weeks or 5 half-lives of that agent before the first dose of MSC1936369B
  2. Subjects meet at least one of the following conditions:

    • Age greater than or equal to 75 years OR
    • Age greater than or equal to 60 and less than 75 years with at least one of the following poor prognostic factors:

      • Secondary AML, as determined by known and documented exposure to leukemogenic therapy or environmental toxin or antecedent history of MDS or MPD according to WHO criteria for at least 3 months prior to trial entry, with prior bone marrow aspirate, biopsy and peripheral blood smear documenting the diagnosis
      • At least one of the following unfavorable cytogenetic abnormalities: del(5q), -5, -7, del(7q), abn 3q, 9q, 11q, 20q, 21q, 17p, t(6;9), t(9;22) or complex karyotypes (greater than or equal to 3 unrelated abnormalities)
      • Eastern Cooperative Oncology Group (ECOG) status 2
  3. Subjects have read and understood the Informed Consent Form and are willing and able to give informed consent. They fully understand requirements of the trial and are willing to comply with all trial visits and assessments
  4. Subjects and their partners must be willing to avoid pregnancy during the trial and until 1 month after the last trial drug administration. Subjects must therefore be willing to use adequate contraception as approved by the Investigator such as two barrier methods or one barrier method with spermicide or intrauterine device, 2 weeks before, during the trial and 1 month after. The use of hormonal contraceptives should be avoided due to a possible drug-drug interaction in female subjects of childbearing age

Exclusion Criteria:

Part 1 and Part 2:

  1. ECOG performance status 3 or greater
  2. Hyperleukocytosis with greater than 30 x 10 to the ninth power per liter leukemia blasts in peripheral blood
  3. Acute promyelocytic leukemia [t(15;17)]
  4. Administration of any antineoplastic therapy within at least 2 weeks or 5 half lives of that therapy of the first MSC1936369B dose; except the use of hydroxyurea as permitted in inclusion criteria
  5. Participation in other clinical trials within at least 2 weeks of the first MSC1936369B dose
  6. Clinical evidence of active central nervous system leukemia
  7. Active and uncontrolled infection including but not limited to known infection with human immunodeficiency virus (HIV), active hepatitis B or hepatitis C. Subjects with an infection receiving treatment with antibiotics may be entered into the trial if they are afebrile and hemodynamically stable for 48 hours prior to trial entry
  8. Major surgery within two weeks prior to trial entry
  9. Liver function tests above the following limits at screening: total bilirubin >1.5 x upper limit of normal (ULN) unless related to Gilbert's syndrome or hemolysis, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >2.5 x ULN, or for subjects with liver involvement AST and/or ALT >5 x ULN
  10. Serum creatinine >1.5 x ULN and /or creatinine clearance <30 milliliter per minute (mL/min) at screening
  11. International normalized ratio (INR) greater than 1.5 x ULN unless on treatment with warfarin
  12. For female subjects: pregnant or breast-feeding
  13. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product
  14. Has significant cardiac conduction abnormalities and/or pacemaker
  15. Has retinal degenerative disease (heredity retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion and/or any medically relevant abnormal findings at the initial ophthalmologic examination
  16. Subjects with solid tumors, for whom the Investigator has clinical suspicion of active disease at the time of enrolment. Patients with adequately treated early stage squamous cell carcinoma of the skin, basal cell carcinoma of the skin, or cervical intraepithelial neoplasia (CIN) are eligible for this study
  17. Signs and symptoms suggestive of transmissible spongiform encephalopathy, or family members who suffer(ed) from such
  18. Other significant disease that in the Investigator's opinion would exclude the subject from the trial
  19. Legal incapacity or limited legal capacity
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00957580

Locations
United States, Illinois
Northwestern University
Chicago, Illinois, United States
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States
United States, Massachusetts
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
United States, Texas
University of Texas - MD Anderson Cancer Center
Houston, Texas, United States
France
Hospital Hotel Dieu, Service D'Hematologie
Nantes, Cedex, France
Hospital Edouard Herriot, Service d'Hematologie Clinique
Lyon Cedex, France
Hospital Saint Louis, Service des Maladies du Sang
Paris, France
CHU du Haut-Leveque, Service des Maladies du Sang Unite de Recherche Clinique
Pessac, France
Sponsors and Collaborators
EMD Serono
Investigators
Study Director: Lars Damstrup, MD Merck KGaA
  More Information

No publications provided

Responsible Party: EMD Serono
ClinicalTrials.gov Identifier: NCT00957580     History of Changes
Other Study ID Numbers: EMR200066_002, 2009-010866-49
Study First Received: August 11, 2009
Last Updated: February 7, 2014
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
United States: Food and Drug Administration

Keywords provided by EMD Serono:
MEK Inhibitor
Pimasertib
Acute Myeloid Leukemia
Hematological Malignancies
Elderly Patients
Phase II

Additional relevant MeSH terms:
Neoplasms
Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Hematologic Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Hematologic Diseases

ClinicalTrials.gov processed this record on April 23, 2014