Clinical Trials /

MLN9708 and Vorinostat in Patients With Advanced p53 Mutant Malignancies

NCT02042989

Description:

The goal of this clinical research study is to find the highest tolerable dose of the combination of MLN9708 and vorinostat that can be given to patients with advanced solid tumors. The safety of these drugs will also be studied.

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: MLN9708 and Vorinostat in Patients With Advanced p53 Mutant Malignancies
  • Official Title: A Phase I Study of MLN9708 and Vorinostat to Target Autophagy in Patients With Advanced p53 Mutant Malignancies

Clinical Trial IDs

  • ORG STUDY ID: 2013-0511
  • SECONDARY ID: NCI-2014-01091
  • NCT ID: NCT02042989

Conditions

  • Advanced Cancers

Interventions

DrugSynonymsArms
MLN9708MLN9708 and Vorinostat
VorinostatSAHA, Suberoylanilide Hydroxamic Acid, MSK-390, ZolinzaMLN9708 and Vorinostat

Purpose

The goal of this clinical research study is to find the highest tolerable dose of the combination of MLN9708 and vorinostat that can be given to patients with advanced solid tumors. The safety of these drugs will also be studied.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, you will be assigned to a dose
      level of MLN9708 and vorinostat based on when you join this study. Up to 4 dose levels of the
      MLN9708 and vorinostat combination will be tested. Up to 6 participants will be enrolled at
      each dose level combination. The first group of participants will receive the lowest dose
      level combination. Each new group will receive a higher dose of either MLN9708 or vorinostat
      than the group before it, if no intolerable side effects were seen. This will continue until
      the highest tolerable dose combination of MLN9708 and vorinostat is found or all 4 dose
      levels are filled. Up to an additional 14 participants will be enrolled in the highest dose
      level of the study drug combination.

      The dose of the study drug combination that you receive may be lowered if you have
      intolerable side effects.

      Study Drug Administration:

      Each study cycle is 28 days.

      You will take MLN9708 capsules by mouth every 7 days (on Days 1, 8, and 15 of every cycle).
      You should swallow MLN9708 capsules whole with 8 ounces (1 cup) of water. Each capsule should
      be swallowed separately with a sip of water. Do not break, chew, or open the capsules. Each
      dose should be taken on an empty stomach, at least 1 hour before or 2 hours after a meal. If
      you miss a dose, take it as soon as you remember, as long as the next scheduled dose is at
      least 72 hours (3 days) away. You should not take a double dose to make up for a missed dose.
      If you vomit after taking a dose, wait until the next scheduled dose. Do not take an
      additional dose.

      You will take vorinostat capsules by mouth on Days 1-21 of each cycle, followed by a break of
      7 days. You should swallow vorinostat capsules whole with water. Do not break, chew, or open
      the capsules. Vorinostat should be taken with food. If you miss a dose, take it as soon as
      you remember, as long as the next scheduled dose is at least 12 hours away. You should not
      take a double dose to make up for a missed dose. If you vomit after taking a dose, wait until
      the next scheduled dose. Do not take an additional dose.

      It is important that you tell your doctor if you have any side effects while on this study.
      If you have side effects or abnormal test results, you may be asked to return to the clinic
      for more tests until the side effects or abnormal test results improve. Your dose of study
      drug may be changed and/or you may be given drugs to help control the side effects.

      Study Visits:

      One (1) time each week during Cycle 1:

      ° Blood (about 6 teaspoons) will be drawn for routine tests and to check your liver and
      kidney function.

      On Day 1 of Cycles 2 and beyond:

        -  You will have a physical exam.

        -  Blood (about 6 teaspoons) will be drawn for routine tests.

        -  If your doctor thinks it is needed, urine will be collected for routine tests.

      At the end of Cycles 2 and beyond:

        -  You will have a CT, PET, and/or MRI scan to check the status of the disease. If your
           doctor thinks it is needed, you may have measurement sooner.

        -  If the study doctor thinks it is needed, blood (about 1 teaspoon) will be drawn to
           measure tumor markers. Tumor markers can be used to check the status of the disease.

      Any time the doctor thinks it is needed:

        -  Blood (about 6 teaspoons) will be drawn for routine tests.

        -  If you can become pregnant, blood (about 1 teaspoon) will be collected for a pregnancy
           test.

        -  You will have an EKG to check your heart function.

      Length of Study:

      You may continue taking the study drugs for as long as the doctor thinks it is in your best
      interest. You will no longer be able to take the study drug if the disease gets worse, if
      intolerable side effects occur, if you develop new health problems, or if you are no longer
      able to follow study directions.

      You may choose to stop taking the study drugs at any time. You should tell the study doctor
      right away if you are thinking about no longer taking part in this study. The study doctor
      will talk to you about how to safely stop taking the study drugs.

      Your participation on the study will be over after the end-of-study visit.

      End of Study Visit:

      Within 30 days after your last dose of the study drugs, the following tests and procedures
      will be performed:

        -  You will have a physical exam.

        -  Blood (about 7 teaspoons) will be drawn for routine tests, tests of your kidney and
           liver function, and tumor marker testing.

        -  You will have a CT, PET, and/or MRI scan to check the status of the disease. If your
           doctor thinks it is needed, you may have a scan performed sooner.

      This is an investigational study. MLN9708 is not FDA approved or commercially available.
      MLN9708 is currently being used for research purposes only. Vorinostat is FDA approved and
      commercially available to treat advanced cutaneous T-cell lymphoma.

      The study doctor can explain how the study drugs are designed to work.

      Up to 56 patients will take part in this study. All will be enrolled at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
MLN9708 and VorinostatExperimentalDose Escalation Phase: Starting Dose of MLN9708 3 mg by mouth on day 1, 8 and 15. Starting Dose of Vorinostat: 100 mg by mouth twice a day, total of 200 mg/day Days 1 to 21. Dose Expansion Phase Starting Doses of MLN9708 and Vorinostat: Maximum tolerated dose from Dose Escalation Phase.
  • MLN9708
  • Vorinostat

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female patients 18 years or older.

          2. 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.

          3. 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 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,
             AND • Must also adhere to the guidelines of any treatment-specific pregnancy
             prevention program, if applicable, OR • Agree to practice true abstinence when this is
             in line with the preferred and usual lifestyle of the subject. (Periodic abstinence
             [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are
             not acceptable methods of contraception.)

          4. Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree
             to one of the following: • Agree to practice effective barrier contraception during
             the entire study treatment period and through 90 days after the last dose of study
             drug, OR • Must also adhere to the guidelines of any treatment-specific pregnancy
             prevention program, if applicable, OR • Agree to practice true abstinence when this is
             in line with the preferred and usual lifestyle of the subject. (Periodic abstinence
             (eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are
             not acceptable methods of contraception.)

          5. Patients must have a diagnosis with solid tumors and lymphomas, either refractory to
             standard therapy or for which no effective standard therapy that conveys clinical
             benefit.

          6. Patients must have a p53 mutation which is defined as cytoplasmic positivity by
             immunohistochemistry and/or next gene mutation sequencing.

          7. Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance
             status 0, 1, or 2.

          8. Patients must meet the following clinical laboratory criteria:Absolute neutrophil
             count (ANC) >/= 1,000/mm^3 and platelet count >/= 75,000/mm^3. Platelet transfusions
             to help patients meet eligibility criteria are not allowed within 3 days before study
             enrollment.Total bilirubin </= 1.5 x the upper limit of the normal range (ULN).Alanine
             aminotransferase (ALT) and aspartate aminotransferase (AST) </= 3 x ULN.Calculated
             creatinine clearance >/= 30 mL/min.

          9. Patients may receive local palliative radiation therapy immediately before or during
             the treatment if the radiation therapy is not delivered to the sole target lesions.

         10. Measurable or evaluable disease will be included as assessed by RECIST 1.1.

        Exclusion Criteria:

          1. Female patients who are lactating or have a positive blood pregnancy test during the
             screening period.

          2. Failure to have fully recovered (ie, </= Grade 1 toxicity) from the reversible effects
             of prior chemotherapy.

          3. Major surgery within 14 days before first dose of study drug..

          4. Radiotherapy within 14 days before first dose of study drug. If the involved field is
             small, 7 days will be considered a sufficient interval between treatment and study
             initiation.

          5. Active uncontrolled central nervous system involvement.

          6. Infection requiring systemic antibiotic therapy or other serious infection within 14
             days before first dose of study drug.

          7. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
             hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
             unstable angina, or myocardial infarction within the past 6 months.

          8. Systemic treatment, within 14 days before the first dose of MLN9708, with strong
             inhibitors of CYP1A2 (fluvoxamine, enoxacin, ciprofloxacin), strong inhibitors of
             CYP3A (clarithromycin, telithromycin, itraconazole, voriconazole, ketoconazole,
             nefazodone, posaconazole) or strong CYP3A inducers (rifampin, rifapentine, rifabutin,
             carbamazepine, phenytoin, phenobarbital), or use of Ginkgo biloba or St. John's wort.

          9. Ongoing or active systemic infection, active hepatitis B or C virus infection, or
             known human immunodeficiency virus (HIV) positive.

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

         11. Known allergy to any of the study medications, their analogues, or excipients in the
             various formulations of any agent.

         12. Known GI disease or GI procedure that could interfere with the oral absorption or
             tolerance of MLN9708 including difficulty swallowing.

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

         14. Patient has >/= Grade 2 peripheral neuropathy

         15. Participation in other clinical trials, including those with other investigational
             agents not included in this trial, within 21days of the start of this trial and
             throughout the duration of this trial.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Doses (MTD) of MLN9708 and Vorinostat
Time Frame:After 2, 28 day cycles
Safety Issue:
Description:Maximum tolerated dose is the highest dose level in which 6 patients have been treated with at most 1 experiencing dose limiting toxicity (DLT). Dose-limiting toxicity defined if the events occur within the first cycle (28 days).

Secondary Outcome Measures

Measure:Tumor Response
Time Frame:4 months
Safety Issue:
Description:Tumor response defined as one or more of the following: (1) stable disease for more than or equal to 4 months, (2) decrease in measurable tumor (sentinel lesions) by more than or equal to 20% by RECIST criteria, (3) decrease in tumor markers by more than or equal to 25% (for example, a ≥ 25% decrease in CA125 for patients with ovarian cancer), or (4) a partial response according to the Choi criteria96-98, i.e. decrease in size by 10% or more, or a decrease in tumor density, as measured by Hounsfield units (HU), by more than or equal to 15%.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Advanced Cancers
  • Advanced solid tumor
  • Advanced p53 Mutant Malignancies
  • MLN9708
  • Vorinostat
  • SAHA
  • Suberoylanilide Hydroxamic Acid
  • MSK-390
  • Zolinza

Last Updated

May 23, 2019