Trial of Pimasertib in Hematological Malignancies
Condition: Leukemia, Myeloid, Acute; Hematologic Neoplasms
MeSH terms: Leukemia; Neoplasms; Hematologic Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute
Intervention: Pimasertib; Pimasertib; Pimasertib; Pimasertib; Pimasertib
Intervention description: 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.; Pimasertib will be administered orally at a dose of 8 mg BID on Days 1 to 21 of a 28-day cycle. The dose will be escalated to 15 mg BID, 23 mg BID, 30 mg BID, 42 mg BID, 45 mg BID, 60 mg BID, 75 mg BID, and 90 mg BID until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.; Pimasertib will be administered orally at a dose of 60 mg BID on Days 1-28 of a 28-day cycle. The dose escalation will proceed to 75 mg BID until MTD is reached. The treatment will be continued until disease progression, intolerable toxicity, or Investigator/subject decision.; 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.; 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.
Intervention MeSH terms: Niacinamide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 81.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: MEK Inhibitor; Pimasertib; Acute Myeloid Leukemia; Hematological Malignancies; Elderly Patients; Phase II

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