Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors
Condition: Locally Advanced Solid Tumor; Metastatic Solid Tumor; Breast Cancer; Non Small Cell Lung Cancer; Melanoma; Colorectal Cancer
MeSH terms: Neoplasms
Intervention: MSC1936369B (pimasertib); SAR245409 (PI3K and mTOR inhibitor); MSC1936369B (pimasertib); SAR245409 (PI3K and mTOR inhibitor)
Intervention description: MSC1936369B (pimasertib) single dose capsule was administered at dose of 15 milligram (mg), 30 mg, 60 mg, 90 mg orally in successive 21-day cycles.Dose escalation was proceeded until Maximum Tolerated Dose (MTD) was reached. Once the MTD was reached, enrollment began in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohorts enrolled subjects with Breast Cancer, Non-Small Cell Lung Cancer (NSCLC), Melanoma, and Colorectal Cancer.; SAR245409 (PI3K and mTOR inhibitor) capsule was administered orally at a dose of 30 mg, 50 mg, 70 mg and 90 mg in successive 21-day cycles. Dose escalation was proceeded until MTD was reached. Once the MTD was reached, enrollment began in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohort enrolled subjects with Breast Cancer, NSCLC, Melanoma, and Colorectal Cancer.; MSC1936369B (pimasertib) capsule was administered twice daily orally at a dose of 60 mg and 45 mg in successive 21-day cycles. Dose escalation proceeded until MTD was reached. The maximum tolerated dose of MSC1936369B (pimasertib) was combined with a lower dose of SAR245409 (PI3K and mTOR inhibitor).; SAR245409 (PI3K and mTOR inhibitor) was administered twice daily orally at a dose of 30 mg and 50 mg in successive 21-day cycles. Dose escalation proceeded until MTD was reached. The maximum tolerated dose of SAR245409 (PI3K and mTOR inhibitor) was combined with a lower dose of MSC1936369B (pimasertib).
Intervention MeSH terms: Niacinamide; Sirolimus; MTOR Inhibitors; Temsirolimus; Elafin
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 146.0
Sex: All
Minimum age: 18 Years
Maximum age: 82 Years
Healthy volunteers: No
Keywords: MEK inhibitor (Pimasertib); PI3K/mTOR Inhibitor; Solid Tumor; Phase I

Summary:

      This research trial is testing a combination of two experimental drugs, MSC1936369B
      (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and
      SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR)
      inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary
      purpose of the study is to determine the maximum tolerated dose of the drug combination.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subject with advanced solid tumors for which there is no approved therapy:

               -  Advanced solid tumor with diagnosed alteration in one or more of the following
                  genes (PTEN, BRAF, KRAS, NRAS, PI3KCA, ErbB1, ErbB2, MET, RET, c-KIT, GNAQ, GNA11
                  and/or

               -  A histologically or cytologically confirmed diagnosis of one of the following
                  solid tumors: pancreatic, thyroid, colorectal, non-small cell lung, endometrial,
                  renal, breast, ovarian carcinoma and melanoma

          -  Subject with archived tumor tissue available for transfer to the Sponsor

          -  Subject enrolled at lower dose level cohorts and MTD expansion cohorts must have tumor
             available for biopsy and agree to pre-treatment and on-treatment tumor biopsies

          -  Subject has measurable or evaluable disease by response evaluation criteria in solid
             tumors (RECIST) v1.1

          -  Subject is aged greater than or equal to (>=) 18 years

          -  Subjects enrolled in disease specific expansion cohorts must fulfill all the
             inclusion/exclusion criteria listed above with the following restriction to the
             Inclusion Criterion number 1:

               -  Relapsed or refractory Kirsten rat sarcoma viral oncogene homolog (KRAS) or
                  neuroblastoma RAS viral oncogene homolog (NRAS) mutated metastatic non-small cell
                  lung cancer (NSCLC) with no approved therapies, or

               -  Relapsed or refractory metastatic triple negative breast cancer defined as
                  estrogen, progesterone and HER2 negative carcinoma of the breast with no approved
                  therapies, or

               -  Relapsed or refractory metastatic colorectal cancer (CRC) with dual KRAS and
                  PIK3CA mutation with no approved therapies, or

               -  BRAF V600E/K mutated unresectable or metastatic melanoma after progression on
                  B-Raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors

          -  Other protocol-defined inclusion criteria could apply

        Exclusion Criteria:

          -  Subject has been previously treated with a PI3K inhibitor or a MEK inhibitor and taken
             off treatment due to treatment related adverse events

          -  Subject has received:

          -  Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, or any other
             anti-cancer therapy within 28 days of trial drug treatment

          -  Any investigational agent within 28 days of trial drug treatment

          -  Extensive prior radiotherapy on more than 30% bone marrow reserves, or prior bone
             marrow/stem cell transplantation

          -  Subject has not recovered from toxicity due to prior therapy

          -  Subject has poor organ and marrow function as defined in the protocol

          -  Subject has a history of central nervous system metastases, unless subject has been
             previously treated for CNS metastases

          -  Subject has a history of difficulty swallowing, malabsorption or other chronic
             gastrointestinal disease

          -  Subject has a history of recent major surgery or trauma within the last 28 days.

          -  Subject has participated in another clinical trial within the past 30 days

          -  Other protocol-defined exclusion criteria could apply