Clinical trial NCT00957580: Trial of Pimasertib in Hematological Malignancies
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leukemia, Myeloid, Acute
Hematologic Neoplasms
Keywords: MEK Inhibitor
Pimasertib
Acute Myeloid Leukemia
Hematological Malignancies
Elderly Patients
Phase II
Lead sponsor: EMD Serono
Sponsor class: INDUSTRY
First posted: 2009-08-12
Enrollment: 81
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an open-label, multi-center, dose-escalation trial of pimasertib (MSC1936369B) 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.


Eligibility 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 pimasertib
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 pimasertib 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 pimasertib 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. Subjects 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

Primary outcomes:
measure: Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs)
timeFrame: Baseline Up to Day 29 of Cycle 1
measure: Part 2: Percentage of Subjects With Best Overall Response
timeFrame: Day 29 of every 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012
Secondary outcomes:
measure: Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation
timeFrame: Baseline up to 3 years
measure: Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose
timeFrame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
measure: Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose
timeFrame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
measure: Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: Part 1: Apparent Terminal Half-Life (t1/2) of Pimasertib: Multiple Dose
timeFrame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
measure: 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) of Pimasertib: Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: 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) of Pimasertib: Multiple Dose
timeFrame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3).
measure: Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: Part 1: Area Under Plasma Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Pimasertib: Multiple Dose
timeFrame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
measure: Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: Part 1: Apparent Oral Clearance (CL/f) of Pimasertib for Pimasertib 75 mg Reporting Arm: Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: Part 1: Apparent Oral Clearance (CL/f) of Pimasertib: Multiple Dose
timeFrame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
measure: Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib:Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib for Pimasertib 75 mg Reporting Arm:Single Dose
timeFrame: Predose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post-dose on Day 1 of cycle 1; Regimen 1, 2 and 3
measure: Part 1: Apparent Oral Volume of Distribution (Vz/f) of Pimasertib: Multiple Dose
timeFrame: Pre dose 0.5, 1.0, 1.5, 2.0, 2.5, 4.0, 6.0, and 10.0 hours post dose in Cycle 1 on Day 19 to Day 21 (Regimen 1 and 2) or Day 26 (Regimen 3)
measure: Part 1: Percentage of Subjects With Best Overall Response
timeFrame: Day 29 of every alternate 29-day cycle until progression reported between day of first subject randomized, September 2009, until cut-off date, December 2012
measure: Part 2: Number of Subjects With TEAEs, Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Houston
country: United States
facility: University of Texas - MD Anderson Cancer Center
state: Texas
city: Nantes
country: France
facility: Hospital Hotel Dieu, Service D'Hematologie
state: Cedex
city: Lyon Cedex
country: France
facility: Hospital Edouard Herriot, Service d'Hematologie Clinique
city: Paris
country: France
facility: Hospital Saint Louis, Service des Maladies du Sang
city: Pessac
country: France
facility: CHU du Haut-Leveque, Service des Maladies du Sang Unite de Recherche Clinique
Study officials:
affiliation: Merck KGaA, Darmstadt, Germany
name: Medical responsible
role: STUDY_DIRECTOR
References: