Clinical Trials /

Sapanisertib, Carboplatin, and Paclitaxel in Treating Patients With Recurrent or Refractory Malignant Solid Tumors

NCT03430882

Description:

This phase I trial studies the sides effects and best dose of sapanisertib, carboplatin, and paclitaxel in treating patients with malignant solid tumors that have come back (recurrent) or do not respond to treatment (refractory). Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing cells, by stopping them from dividing, or by stopping them from spreading. Giving sapanisertib, carboplatin, and paclitaxel may work better in treating patients with malignant solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Sapanisertib, Carboplatin, and Paclitaxel in Treating Participants With Recurrent or Refractory Malignant Solid Tumors
  • Official Title: A Phase I Study of TAK-228 (MLN0128) in Combination With Carboplatin Plus Paclitaxel in Patients With Advanced Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2016-0845
  • SECONDARY ID: NCI-2018-00989
  • SECONDARY ID: 2016-0845
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03430882

Conditions

  • Recurrent Malignant Solid Neoplasm
  • Refractory Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboTreatment (sapanisertib, paclitaxel, carboplatin)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratTreatment (sapanisertib, paclitaxel, carboplatin)
SapanisertibINK-128, INK128, MLN-0128, MLN0128, TAK-228Treatment (sapanisertib, paclitaxel, carboplatin)

Purpose

This phase I trial studies the sides effects and best dose of sapanisertib, carboplatin, and paclitaxel in treating participants with malignant solid tumors that have come back or do not respond to treatment. Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing cells, by stopping them from dividing, or by stopping them from spreading. Giving sapanisertib, carboplatin, and paclitaxel may work better in treating participants with malignant solid tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the safety and tolerability of the combination of sapanisertib (TAK-228
      [MLN0128]) plus paclitaxel, when given with carboplatin, and to determine the optimal dose
      triplet, or maximum tolerated dose (MTD), in patients with advanced cancers refractory to
      standard therapy.

      SECONDARY OBJECTIVES:

      I. To assess the clinical tumor response of this combination. II. To assess toxicity of this
      combination. III. To assess progression free survival. IV. To assess molecular signatures
      predictive of sensitivity and resistance.

      OUTLINE: This is a dose escalation study.

      Participants receive sapanisertib orally (PO) once daily (QD) on days 2-4, 9-11, and 16-18,
      paclitaxel intravenously (IV) over 3 hours on days 1, 8, and 15, and carboplatin IV over 60
      minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of
      disease progression or unacceptable toxicity. Participants then receive sapanisertib PO QD on
      days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, participants are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (sapanisertib, paclitaxel, carboplatin)ExperimentalParticipants receive sapanisertib PO QD on days 2-4, 9-11, and 16-18, paclitaxel IV over 3 hours on days 1, 8, and 15, and carboplatin IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Participants then receive sapanisertib PO QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Paclitaxel
  • Sapanisertib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a diagnosis of a solid tumor malignancy and is refractory to
             standard therapies who have relapsed after standard therapy, or whose cancers have no
             standard therapy.

          -  Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
             status =< 1.

          -  Female patients 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 1 effective method of contraception and 1 additional effective (barrier)
             method, at the same time, from the time of signing the informed consent through 90
             days (or longer as mandated by local labeling [e.g., United Surgical Partners
             International (USPI), summary of product characteristics (SmPC), etc,]) 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 patient (Periodic abstinence [e.g., calendar,
             ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and
             lactational amenorrhea are not acceptable methods of contraception. Female and male
             condoms should not be used together.)

          -  Male patients, even if surgically sterilized (i.e., status post-vasectomy), who: agree
             to practice highly effective barrier contraception during the entire study treatment
             period and through 120 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
             patient. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation
             methods for the female partner], withdrawal, spermicides only, and lactational
             amenorrhea are not acceptable methods of contraception. Female and male condoms should
             not be used together.) Agree not to donate sperm during the course of this study or
             within 120 days after receiving their last dose of study drug.

          -  Absolute neutrophil count (ANC) >= 1.5 x 10^9/L.

          -  Platelet count >= 100 x 10^9/L.

          -  Hemoglobin >= 9 g/dL without transfusion within 1 week preceding study drug
             administration.

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN).

          -  Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase
             [AST/SGOT] and alanine aminotransferase/serum glutamic pyruvic transaminase
             [ALT/SGPT]) =< 2.5 x ULN (=< 5 x ULN if liver metastases are present).

          -  Creatinine clearance >=50 mL/min based either on Cockcroft-Gault estimate or based on
             urine collection (12 or 24 hour).

          -  Glycosylated hemoglobin (HbA1c) < 7%.

          -  Fasting serum glucose =< 130 mg/dL.

          -  Fasting triglycerides =< 300 mg/dL.

          -  Ability to swallow oral medications.

          -  Voluntary written consent must be given before performance of any study related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the patient at any time without prejudice to future medical care.

          -  Patients who have a history of brain metastasis are eligible for the study provided
             that all the following criteria are met: a) Brain metastases which have been treated
             b) No evidence of disease progression for >= 3 months before the first dose of study
             drug. c) No hemorrhage after treatment d) Off-treatment with dexamethasone for 4 weeks
             before administration of the first dose of TAK-228 e) No ongoing requirement for
             dexamethasone or anti-epileptic drugs.

          -  Patients must have evaluable or measurable disease by Response Evaluation Criteria in
             Solid Tumors (RECIST) 1.1 criteria.

          -  Patients must be 4 weeks beyond previous treatment of any chemotherapy or
             radiotherapy, and must have recovered to =< grade 1 or previous baseline for each
             toxicity. Exception: Patients may have received palliative low dose radiotherapy to
             the limbs 1-4 weeks before this therapy provided pelvis, sternum, scapulae, vertebrae,
             or skull were not included in the radiotherapy field. Patients who have received
             non-chemotherapeutic biological agents will need to wait at least 5 half-lives or 4
             weeks, whichever is shorter, from the last day of treatment of non-chemotherapeutic
             biological agents.

        Exclusion Criteria:

          -  Carboplatin or paclitaxel exposure within past 6 months.

          -  Central nervous system (CNS) metastasis.

          -  Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,
             active central nervous system disease, active infection, or any other condition that
             could compromise the patient's participation in the study.

          -  Known history of human immunodeficiency virus infection.

          -  Known history of hepatitis B surface antigen-positive, or known or suspected active
             hepatitis C infection.

          -  Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of treatment according to this protocol.

          -  Diagnosed or treated for another malignancy within 2 years before administration of
             the first dose of study drug, or previously diagnosed with another malignancy and have
             any evidence of residual disease. Patients with non-melanoma skin cancer or carcinoma
             in situ of any type are not excluded if they have undergone complete resection.

          -  Breast feeding or pregnant.

          -  Treatment with any investigational products within 4 weeks before the first dose of
             study drug.

          -  Previous treatment with dual PI3K/mTOR inhibitors, TORC1/2 inhibitors or TORC1
             inhibitors.

          -  Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI
             disease, or for an unknown reason that may alter the absorption of TAK-228. In
             addition, patients with enteric stomata are also excluded.

          -  History of any of the following within the last 6 months before administration of the
             first dose of the drug: a) Ischemic myocardial event, including angina requiring
             therapy and artery revascularization procedures b) Ischemic cerebrovascular event,
             including transient ischemic attack and artery revascularization procedures c)
             Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
             cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or
             ventricular tachycardia) d) Placement of a pacemaker for control of rhythm e) New York
             Heart Association (NYHA) class III or IV heart failure f) Pulmonary embolism.

          -  Significant active cardiovascular or pulmonary disease including: a) Uncontrolled
             hypertension (i.e., systolic blood pressure > 150 mm Hg, diastolic blood pressure > 90
             mm Hg). Use of anti-hypertensive agents to control hypertension before cycle 1 day 1
             is allowed. b) Pulmonary hypertension c) Uncontrolled asthma or oxygen (O2) saturation
             < 90% by arterial blood gas analysis or pulse oximetry on room air d) Significant
             valvular disease; severe regurgitation or stenosis by imaging independent of symptom
             control with medical intervention, or history of valve replacement e) Medically
             significant (symptomatic) bradycardia f) History of arrhythmia requiring an
             implantable cardiac defibrillator g) Baseline prolongation of the rate-corrected QT
             interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or
             history of congenital long QT syndrome, or torsades de pointes).

          -  Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%;
             patients with a history of transient glucose intolerance due to corticosteroid
             administration may be enrolled in this study if all other inclusion/exclusion criteria
             are met.

          -  Patients receiving systemic corticosteroids (either IV or oral steroids, excluding
             inhalers or low-dose hormone replacement therapy) within 1 week before administration
             of the first dose of study drug.

          -  Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within
             7 days before receiving the first dose of study drug.

          -  Patients with hypersensitivity or other allergic reaction to platinum chemotherapy.

          -  Patients with hypersensitivity or other allergic reaction to taxanes.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence and grade of adverse events graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v.) 4.03
Time Frame:Up to 30 days after last dose
Safety Issue:
Description:Wilcoxon's Signed-Rank Test and Fisher's exact test will be used for data analysis of continuous variables and categorical variables, respectively. A mixed model accounting for patient effects will be used to analyze longitudinal data over time. Descriptive statistics will be provided on the grade and type of toxicity by dose level.

Secondary Outcome Measures

Measure:Clinical tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
Time Frame:Up to 5 years
Safety Issue:
Description:All of the patients who meet the eligibility criteria will be included in the main analysis of the response rate. Patients in response categories 3-8 should be considered as failing to respond to therapy (disease progression). A patient will be determined as having a response if he/she has complete response (CR), partial response (PR). Additionally, a patient with CR, PR, or stable disease (SD) for at least 6 cycles will be considered as having clinical benefit. A patient will be determined as a non-response if there is SD for less than 6 cycles or no evidence of response by 6 cycles during this study. Wilcoxon's Signed-Rank Test and Fisher's exact test will be used for data analysis of continuous variables and categorical variables, respectively. A mixed model accounting for patient effects will be used to analyze longitudinal data over time. Descriptive statistics will be provided on the grade and type of toxicity by dose level.
Measure:Progression-free survival as defined by RECIST v.1.1
Time Frame:Up to 5 years
Safety Issue:
Description:
Measure:Molecular signatures predictive of sensitivity and resistance
Time Frame:Up to 5 years
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

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