Clinical Trials /

Vorinostat and Temsirolimus With or Without Radiation Therapy in Treating Younger Patients With Newly Diagnosed or Progressive Diffuse Intrinsic Pontine Glioma

NCT02420613

Description:

This phase I trial studies the side effects and best dose of temsirolimus when given together with vorinostat and with or without radiation therapy in treating younger patients with newly diagnosed or progressive diffuse intrinsic pontine glioma, a tumor that arises from the middle portion of the brain stem. Vorinostat and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving temsirolimus and vorinostat with or without radiation therapy may be a better treatment for younger patients with diffuse intrinsic pontine glioma.

Related Conditions:
  • Diffuse Intrinsic Pontine Glioma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Vorinostat and Temsirolimus With or Without Radiation Therapy in Treating Younger Patients With Newly Diagnosed or Progressive Diffuse Intrinsic Pontine Glioma
  • Official Title: A Phase I Study of Suberoylanilide Hydroxamic Acid (SAHA, Vorinostat) With Temsirolimus in Children With Newly Diagnosed or Progressive Diffuse Intrinsic Pontine Glioma (DIPG)

Clinical Trial IDs

  • ORG STUDY ID: 2014-0135
  • SECONDARY ID: NCI-2015-00817
  • SECONDARY ID: 2014-0135
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02420613

Conditions

  • Diffuse Intrinsic Pontine Glioma

Interventions

DrugSynonymsArms
TemsirolimusCCI-779, CCI-779 Rapamycin Analog, Cell Cycle Inhibitor 779, Rapamycin Analog, Rapamycin Analog CCI-779, ToriselArm I (vorinostat, radiation therapy, temsirolimus)
VorinostatL-001079038, MSK-390, SAHA, Suberanilohydroxamic Acid, Suberoylanilide Hydroxamic Acid, ZolinzaArm I (vorinostat, radiation therapy, temsirolimus)

Purpose

This phase I trial studies the side effects and best dose of temsirolimus when given together with vorinostat and with or without radiation therapy in treating younger patients with newly diagnosed or progressive diffuse intrinsic pontine glioma, a tumor that arises from the middle portion of the brain stem. Vorinostat and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving temsirolimus and vorinostat with or without radiation therapy may be a better treatment for younger patients with diffuse intrinsic pontine glioma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the maximum tolerated dose (MTD) or recommended phase 2 dose of temsirolimus
      in combination with vorinostat given every four weeks in patients with diffuse intrinsic
      pontine glioma (DIPG).

      II. To define and describe the toxicities of the combination vorinostat and temsirolimus
      administered on this schedule.

      SECONDARY OBJECTIVES:

      I. To define the antitumor activity of the combination of vorinostat and temsirolimus within
      the confines of a phase 1 study.

      II. To assess the biologic effects of vorinostat and temsirolimus on the signaling pathways
      of interest in these tumors.

      III. To evaluate response with advanced neuroimaging (including magnetic resonance
      spectroscopy) and correlate with fiber tract changes using tractography and fractional
      anisotropy.

      OUTLINE: This is a dose-escalation study of temsirolimus. Patients are assigned to 1 of 2
      treatment arms.

      ARM I:

      CHEMORADIOTHERAPY PHASE: Patients receive vorinostat once daily (QD) and undergo radiation
      therapy QD for 30 fractions over 6-7 weeks.

      MAINTENANCE PHASE: Four to six weeks after the completion of radiation therapy, patients
      receive vorinostat PO QD and temsirolimus intravenously (IV) over 30-90 minutes on days 1-8.
      Treatment repeats every 28 days for 10 cycles in the absence of disease progression or
      unacceptable toxicity.

      ARM II: Patients receive vorinostat PO QD and temsirolimus IV over 30-90 minutes on days 1-8.
      Treatment repeats every 28 days for 12 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 3, 6, 9, and 12 months.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (vorinostat, radiation therapy, temsirolimus)ExperimentalCHEMORADIOTHERAPY PHASE: Patients receive vorinostat QD and undergo radiation therapy QD for 30 fractions over 6-7 weeks. MAINTENANCE PHASE: Four to six weeks after the completion of radiation therapy, patients receive vorinostat PO QD and temsirolimus IV over 30-90 minutes on days 1-8. Treatment repeats every 28 days for 10 cycles in the absence of disease progression or unacceptable toxicity.
  • Temsirolimus
  • Vorinostat
Arm II (vorinostat, temsirolimus)ExperimentalPatients receive vorinostat PO QD and temsirolimus IV over 30-90 minutes on days 1-8. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Temsirolimus
  • Vorinostat

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with newly diagnosed or progressive DIPG as confirmed by gadolinium enhanced
             magnetic resonance imaging (MRI) are eligible; MRI must demonstrate that at least 2/3
             of the tumor is situated in the pons and that the origin of the tumor is clearly in
             the pons; biopsy is not required; tumors with features not typical of diffuse
             intrinsic brainstem glioma are not eligible; these include dorsally exophytic
             brainstem gliomas, cervicomedullary junction tumors, and focal low grade gliomas of
             the midbrain or brainstem which should undergo resection and pathologic evaluation;
             patients, who have received re-irradiation for progression of the tumor, will be
             eligible if they show evidence of measurable progressive disease after the
             re-irradiation; patients at diagnosis with involvement of the spine will not be
             eligible, however if at progression features of spine involvement are present they
             will be eligible for stratum II

          -  Patients must have a Karnofsky greater than or equal to 50% for patients > 16 years of
             age and Lansky greater than or equal to 50 for patients less than or equal to 16 years
             of age; patients who are unable to walk because of paralysis, but who are up in a
             wheelchair, will be considered ambulatory for the purpose of assessing the performance
             score

          -  Patients must have fully recovered from the acute toxic effects of all prior
             anti-cancer chemotherapy or radiation to grade 2 or less

          -  Patients must not have received myelosuppressive therapy within 3 weeks of enrollment
             onto this study (6 weeks if prior nitrosourea)

          -  At least 14 days must have passed after the last dose of a long-acting growth factor
             (e.g. Neulasta) or 7 days for short-acting growth factor

          -  At least 7 days must have elapsed after the last of a biologic agent that is not a
             monoclonal antibody, to be enrolled on this study

          -  At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor
             vaccines

          -  At least 3 half-lives must have elapsed after treatment with a monoclonal antibody and
             enrollment on this study

          -  Greater than or equal to 2 weeks must have elapsed for local palliative radiotherapy
             (re-irradiation for progressive disease or upfront radiation therapy [RT] at initial
             diagnosis) and enrollment on study for stratum II; at least 24 weeks must have elapsed
             if patient received craniospinal radiotherapy due to any other prior malignancies

          -  The patient must have no evidence of active graft vs. host disease, and greater than
             or equal to 12 weeks must have elapsed since transplant or stem cell infusion and
             enrollment on this study for any other pathology

          -  Prior treatment with vorinostat is allowed but at least 3 weeks must have elapsed from
             the last dose and effects of prior therapy have resolved

          -  Patients with central nervous system (CNS) tumors who are receiving steroids are
             eligible

          -  Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/microL

          -  Platelet count greater than or equal to 100,000/microL (transfusion independent)

          -  Hemoglobin greater than or equal to 10.0 gm/dL (transfusion independent)

          -  Serum creatinine less than or equal to 1.5 x institutional upper limit of normal for
             age

          -  Bilirubin (sum of conjugated + unconjugated) less than 1.5 x upper limit of normal
             (ULN) for age

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) less
             than or equal to 110 U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

          -  Serum albumin must be greater than or equal to 2 g/dL

          -  Prothrombin time (PT) and international normalized ratio (INR) < 1.2 x ULN

          -  Patients with seizure disorder may be enrolled if on non-enzyme inducing
             anticonvulsants and well controlled

          -  Serum cholesterol and serum triglyceride levels must be less than 300 mg/dl

          -  Females > 13 years of age or who have achieved menarche must have a negative pregnancy
             test within 2 weeks of starting treatment (urine or serum) to be eligible and if
             sexually active must also agree to use contraception; male sexually active patients
             must agree to use an effective method of contraception

          -  Patient's current disease state must be one for which there is no known curative
             therapy or therapy proven to prolong survival with an acceptable quality of life

          -  Patients must have a life expectancy of greater than or equal to 2 months; neurologic
             deficits in patients with CNS tumors must have been relatively stable for a minimum of
             1 week prior to starting protocol therapy

        Exclusion Criteria:

          -  Patients with other malignancies will not be eligible for stratum I or II; patients
             with disseminated disease including to the spine will not be eligible for stratum 1
             but will be eligible for stratum II

          -  Patients must not have a history of myocardial infarction, severe or unstable angina,
             clinically significant peripheral vascular disease, grade 2 or greater heart failure,
             or serious and inadequately controlled cardiac arrhythmia

          -  Pregnant or breast-feeding women will not be entered on this study

          -  Patients who are currently receiving enzyme inducing anticonvulsants are not eligible

          -  Patients who are currently receiving therapeutic anticoagulants (including aspirin,
             low molecular weight heparin, and others) are not eligible

          -  Patients who are currently receiving angiotensin-converting enzyme (ACE) inhibitors
             are not eligible due to the development of angioneurotic edema-type reactions in some
             subjects who received concurrent treatment with temsirolimus + ACE inhibitors

          -  Patients who are receiving cyclosporine, tacrolimus or other agents to prevent either
             graft-versus-host disease post bone marrow transplant or organ rejection
             post-transplant are not eligible for this trial

          -  Patients with history of allergic reactions attributed to compounds of similar
             chemical; or biologic composition to vorinostat or temsirolimus are not eligible

          -  Patients who have an uncontrolled infection are not eligible

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study are not eligible

          -  Patients with newly diagnosed DIPG who have received vorinostat previously will not be
             eligible for stratum I; patients with progressive DIPG will be eligible if they have
             received either one of the two drugs vorinostat or temsirolimus but will not be
             eligible for stratum II if have received both the drugs before
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:7 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of temsirolimus
Time Frame:28 days (course 1)
Safety Issue:
Description:MTD will be defined as the highest dose studied in which six patients have been treated and at most two patients with dose limiting toxicities (DLTs) are observed. DLTs will be monitored for the first course of the combination of vorinostat and temsirolimus.

Secondary Outcome Measures

Measure:Radiographic response
Time Frame:Up to 12 months
Safety Issue:
Description:Will be evaluated using the Response Evaluation Criteria in Solid Tumors from the National Cancer Institute. Best response will be tabulated by dose and category (complete response, partial response, stable disease and progressive disease).

Details

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

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