Trial of Pimasertib in Hematological Malignancies

NCT00957580 | Terminated Phase 2 Results DMC

• 2 other identifiers: EMR200066_0022009-010866-49
• Study Type: interventional
• Target: 81
• Locations: 2 countries
• Sites: 9

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.

Conditions

Leukemia, Myeloid, Acute; Hematologic Neoplasms

Keywords

MEK Inhibitor; Pimasertib; Acute Myeloid Leukemia; Hematological Malignancies; Elderly Patients; Phase II

Outcome Measures

Primary Outcomes (2)

• Part 1: Number of Subjects With Dose Limiting Toxicities (DLTs)

  The DLT was any toxicity that resulted in treatment delay for more than (\>) 2 weeks due to treatment-related adverse effects, or any Grade greater than or equal to (\>=) 3 non-hematological toxicity excluding Grade 4 asymptomatic increases in liver function tests reversible within 7 days in subjects with liver involvement, and Grade 3 asymptomatic increases in liver function tests reversible within 7 days for subjects without liver involvement, Grade 3 vomiting unless encountered and persistent for more than 3 days despite adequate and optimal therapy, and Grade 3 diarrhea unless encountered and persistent for more than 3 days despite adequate and optimal anti-diarrhea therapy at any DL and judged to be possibly or probably related to the trial treatment by the Investigator and/or the Sponsor.

  Baseline Up to Day 29 of Cycle 1

• Part 2: Percentage of Subjects With Best Overall Response

  The best overall response was to be reported as either of the following: (1) Morphologic complete remission (CR) = normalization of the peripheral blood absolute neutrophil count (PBANC) \>1.0x10\^9 per liter (/L), platelets \>100x10\^9 /L, bone marrow aspirate with less than or equal to (\<=) 5 percent (%) blasts, no blasts with Auer rods (AML only). (2) Complete remission with incomplete blood count recovery (CRi) = Same as CR without normalization of PBANC and platelet count. (3) Partial remission (PR) = normalization of PBANC \>1.0x10\^9/L, platelets \>100x10\^9/L, and at least a 50% decrease in the percentage of marrow aspirate blasts to 5-25%, or marrow blasts less than (\<) 5%. (4) Progressive disease (PD) = \>50% increase in peripheral blood or bone marrow blasts. (5) Stable disease (SD) = subjects who failed to achieve CR, CRi or PR and without criteria for PD.

  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 (19)

• Part 1: Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death and TEAEs Leading to Permanent Treatment Discontinuation

  Baseline up to 3 years

• Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Single Dose

  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

• Part 1: Maximum Plasma Concentration (Cmax) of Pimasertib Multiple Dose

  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).

• Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Single Dose

  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

• Part 1: Time to Reach Maximum Plasma Concentration (Tmax): Multiple Dose

  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)

Study Arms (5)

Regimen 1 (Part 1)

EXPERIMENTAL

Drug: Pimasertib

Regimen 2 (Part 1)

EXPERIMENTAL

Drug: Pimasertib

Regimen 3 (Part 1)

EXPERIMENTAL

Drug: Pimasertib

Regimen 1 (Part 2)

EXPERIMENTAL

Drug: Pimasertib

Regimen 2 (Part 2)

EXPERIMENTAL

Drug: Pimasertib

Interventions

Pimasertib DRUG

Pimasertib will be administered orally at a dose of 8 mg twice daily (BID) on Days 1 to 5, 8 to 12, 15 to 19, and 22 to 26 of a 28-day cycle. The dose will be escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 60 mg BID, and 75 mg BID) until Maximum Tolerated Dose (MTD) is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.

Also known as: MSC1936369B

Regimen 1 (Part 1)

Eligibility Criteria

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

You may qualify if:

• Part 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:
• Subjects with second or subsequent relapse after standard therapy, for whom no established treatment options are available
• Subjects refractory to available therapies, for example, who failed to achieve complete response (CR) after 2 induction chemotherapy treatments
• 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
• Age greater than or equal to 18 years
• 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
• 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:
• 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:

You may not qualify if:

• Part 1 and Part 2:
• ECOG performance status 3 or greater
• Hyperleukocytosis with greater than 30 x 10 to the ninth power per liter leukemia blasts in peripheral blood
• Acute promyelocytic leukemia \[t(15;17)\]
• Participation in other clinical trials within at least 2 weeks of the first pimasertib dose
• Clinical evidence of active central nervous system leukemia
• 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
• Major surgery within two weeks prior to trial entry
• 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
• Serum creatinine \>1.5 x ULN and /or creatinine clearance \<30 milliliter per minute (mL/min) at screening
• International normalized ratio (INR) greater than 1.5 x ULN unless on treatment with warfarin
• For female subjects: pregnant or breast-feeding
• History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease or conditions that may hamper compliance and/or absorption of the tested product
• Has significant cardiac conduction abnormalities and/or pacemaker
• 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

Sponsors & Collaborators

• EMD Serono: lead

Study Sites (9)

Northwestern University

Chicago, Illinois, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Location

University of Texas - MD Anderson Cancer Center

Houston, Texas, United States

Location

Hospital Hotel Dieu, Service D'Hematologie

Nantes, Cedex, France

Location

Hospital Edouard Herriot, Service d'Hematologie Clinique

Lyon, France

Location

Hospital Saint Louis, Service des Maladies du Sang

Paris, France

Location

CHU du Haut-Leveque, Service des Maladies du Sang Unite de Recherche Clinique

Pessac, France

Location

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Hematologic Neoplasms

Interventions

N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms by Site

Limitations and Caveats

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).

Results Point of Contact

• Title: Merck KGaA Communication Center
• Organization: Merck Serono, a division of Merck KGaA

service@merckgroup.com

+49-6151-72-5200

Study Officials

• Medical responsible

  Merck KGaA, Darmstadt, Germany

  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: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 11, 2009
• First Posted: August 12, 2009
• Study Start: September 30, 2009
• Primary Completion: December 31, 2012
• Study Completion: December 31, 2012
• Last Updated: August 21, 2017
• Results First Posted: March 29, 2017

Record last verified: 2017-07

Locations

US (5); FR (4)