A Safety, Tolerability, and Pharmacokinetics Study of MLN0128 as a Single Agent and in Combination With Paclitaxel in Adults With Advanced Nonhematologic Malignancies
Condition: Non-hematologic Malignancy
MeSH terms: Neoplasms
Intervention: Sapanisertib; Paclitaxel
Intervention description: Sapanisertib capsules; Paclitaxel injection
Intervention MeSH terms: Paclitaxel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 61.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      The purposes of this study are to evaluate the safety and tolerability of sapanisertib
      (MLN0128) milled active pharmaceutical ingredient (API) capsules administered both as a
      single agent and in combination with paclitaxel, to characterize the effect of a high-fat
      meal on the pharmacokinetics (PK) of sapanisertib milled API capsules, and to characterize
      the PK of sapanisertib milled API capsules when administered on an empty stomach
      approximately 24 hours after paclitaxel infusion.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age is ≥ 18 years, including males and females.

          2. Has Advanced nonhematologic malignancies, with the exception of primary brain tumor,
             and have failed or are not eligible for standard of care therapy. History of brain
             metastasis may be allowed if all the following criteria are met: brain metastases have
             been treated, there is no evidence of progression or hemorrhage after treatment,
             dexamethasone discontinued for ≥ 4 weeks before first study drug administration, and
             there is no ongoing requirement for dexamethasone or anti-epileptic drugs.

          3. Has received not more than 4 prior lines of systemic cytotoxic chemotherapy for
             advanced or metastatic disease.

          4. Has Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.

          5. Has adequate organ function, including the following:

               -  Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥ 1.5 x
                  10^9/L; platelet count ≥ 100 x 10^9/L; and hemoglobin ≥ 9 g/dL without
                  transfusion in the last 2 weeks

               -  Hepatic: total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN),
                  transaminases (aspartate aminotransferase [AST]/serum glutamic oxaloacetic
                  transaminase [SGOT] and alanine aminotransferase [ALT]/serum glutamic pyruvic
                  transaminase [SGPT]) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present)

               -  Renal: normal serum creatinine or calculated creatinine clearance ≥ 60 mL/min
                  based either on Cockcroft-Gault estimate or based on urine collection (12- or
                  24-hour)

               -  Metabolic: fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300
                  mg/dL

          6. Has left ventricular ejection fraction (LVEF) within 5 absolute percentage points of
             institutional standard of normal as measured by echocardiogram (ECHO) or multiple
             gated acquisition scan (MUGA) within 4 weeks before first study drug administration
             (ie, if the institutional normal is 50%, participant's LVEF may be as low as 45% to be
             eligible for the study).

          7. Is a female participants who:

               -  Are postmenopausal for at least 1 year before the screening visit, OR

               -  Are surgically sterile, OR

               -  If they are of childbearing potential, agree to practice 2 effective methods of
                  contraception, at the same time, from the time of signing the informed consent
                  form through 90 days after the last dose of study drug, or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence (eg, calendar,
                  ovulation, symptothermal, postovulation methods] and withdrawal are not
                  acceptable methods of contraception.)

             Male participants, even if surgically sterilized (ie, status postvasectomy), who:

               -  Agree to practice effective barrier contraception during the entire study
                  treatment period and through 90 days after the last dose of study drug, or

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the participant. (Periodic abstinence [eg, calendar,
                  ovulation, symptothermal, postovulation methods for the female partner] and
                  withdrawal are not acceptable methods of contraception.)

          8. Has ability to swallow oral medications.

          9. Has voluntary written consent obtained before performance of any study-related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the participant at any time without prejudice to future medical care.

        Exclusion Criteria:

          1. Has a diagnosis of primary brain tumor.

          2. Has untreated brain metastasis or history of leptomeningeal disease or spinal cord
             compression.

          3. Has failed to recover from the reversible effects of prior anticancer therapies with
             the exception of alopecia, and after-effects associated with prior tyrosine kinase
             inhibitor therapy, such as hair depigmentation, hypothyroidism, and/or splinter
             hemorrhage.

          4. Has received prior cancer therapy or other investigational therapy within 2 weeks
             before the first administration of study drug. For prior therapies with a half-life
             longer than 3 days, the interval must be at least 28 days before the first
             administration of study drug, and the participant must have documented disease
             progression.

          5. Has initiation of hematopoietic growth factors within 1 week before the first
             administration of any study drug; participants already receiving hematopoietic growth
             factors on a chronic basis for ≥ 4 weeks are eligible.

          6. Has chronic systemic corticosteroid (except inhalers) use within 1 week before the
             first administration of study drug. Premedication with dexamethasone before paclitaxel
             administration in this study is allowed.

          7. Has manifestations of malabsorption due to prior gastrointestinal surgery,
             gastrointestinal disease, or for an unknown reason that may alter the absorption of
             MLN0128.

          8. Has poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >
             7%; participants with a history of transient glucose intolerance due to corticosteroid
             administration are allowed if all other eligibility criteria are met.

          9. Has other clinically significant comorbidities, such as uncontrolled pulmonary
             disease, active central nervous system disease, active infection, or any other
             condition that could compromise the participant's participation in the study.

         10. Has a known human immunodeficiency virus infection.

         11. Is pregnant (positive serum or urine pregnancy test) or breastfeeding.

         12. Has any history of unstable angina, myocardial infarction, New York Heart Association
             Class III or IV heart failure, and/or pulmonary hypertension.

         13. Has significant active cardiovascular disease including:

               -  Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mmHg,
                  diastolic blood pressure > 95 mmHg)

               -  Grade 3 or higher valvular disease

               -  Grade 3 or higher atrial fibrillation

               -  Grade 3 or higher bradycardia

               -  Endocarditis

               -  Pulmonary embolism

               -  Recent cerebrovascular accident/transient ischemic attack ≤ 6 months before
                  enrollment

         14. Diagnosed or treated for another malignancy within 2 years before the first dose or
             previously diagnosed with another malignancy and have any evidence of residual
             disease. Participants with nonmelanoma skin cancer or carcinoma in situ of any type
             are not excluded if they have undergone complete resection.

         15. Single-Agent QD Arm participants participating in the pharmacokinetic (PK) Run-In
             (only): participants who use proton pump inhibitors (PPIs) less than 5 days before the
             first MLN0128 PK Run-In dose OR use H2 receptor antagonists within 24 hours of the
             first PK Run-In dose.