Trial of Pimasertib in Hematological Malignancies

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