Vorinostat in Combination With Chemotherapy in Relapsed/Refractory Solid Tumors and CNS Malignancies

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Brief Title

Vorinostat in Combination With Chemotherapy in Relapsed/Refractory Solid Tumors and CNS Malignancies

Official Title

A Phase I Study of Vorinostat in Combination With Vincristine, Irinotecan, and Temozolomide in Children, Adolescents, and Young Adults With Relapsed or Refractory Solid Tumors and CNS Malignancies

Brief Summary

      Investigators are testing new experimental drug combinations such as the combination of
      vorinostat, vincristine, irinotecan, and temozolomide in the hopes of finding a drug that may
      be effective against tumors that have come back or that have not responded to standard
      therapy.

      The goals of this study are:

        -  To find the highest safe dose of vorinostat that can be given together with vincristine,
           irinotecan, and temozolomide without causing severe side effects;

        -  To learn what kind of side effects this four drug combination can cause;

        -  To learn about the effects of vorinostat and the combination of vorinostat, vincristine,
           irinotecan, and temozolomide on specific molecules in tumor cells;

        -  To determine whether the combination of vorinosat, vincristine, irinotecan, and
           temozolomide is a beneficial treatment.
    

Detailed Description

      This first cycle will be used to determine whether the patient can tolerate the
      chemotherapeutic backbone without developing a DLT. The baseline disease evaluation will be
      obtained following hematologic recovery from the first cycle of chemotherapy, after which
      combination therapy with vorinostat will be given in subsequent cycles (2-12) w/
      modifications if needed. Vorinostat dose escalation in subsequent patient cohorts will occur
      based on DLT to determine a MTD.
    

Study Phase

Phase 1

Study Type

Interventional


Primary Outcome

To determine a maximally tolerated (or optimal) dose of vorinostat

Secondary Outcome

 Overall response rate (ORR) after therapy

Condition

Ewing Sarcoma

Intervention

Vorinostat

Study Arms / Comparison Groups

 Vorinostat
Description:  The first cycle of chemotherapy will not include the experimental agent vorinostat. This first cycle will be used to determine whether the patient can tolerate the chemotherapeutic backbone without developing a DLT.
Cycle 1
Vincristine: 1.5 mg/m2/day (maximum dose 2 mg) IV Days 1 and 8 over 1-15 minutes.
Temozolomide: 125 mg/m2/day PO Days 1-5.
Irinotecan: 50 mg/m2/day IV Days 1-5 over 60 minutes.
Cefixime: 8 mg/kg/day (maximum dose 400 mg) PO. Begin 2 days prior to irinotecan therapy and continue through Day 8.
Cycles 2-12
Vincristine: 1.5 mg/m2/day (maximum dose 2 mg) IV Days 1 and 8 over 1-15 minutes.
Temozolomide: 125 mg/m2/day PO Days 1-5.
Irinotecan: 50 mg/m2/day IV Days 1-5 over 60 minutes.
Cefixime: 8 mg/kg/day (maximum dose 400 mg) PO. Begin 2 days prior to irinotecan therapy and continue through Day 8.
Vorinostat: Dose per escalation schema daily Days 1-5.
Vorinostat will not be administered during Cycle 1.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

30

Start Date

March 17, 2017

Completion Date

December 17, 2022

Primary Completion Date

December 17, 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Age: Patients must be less than or equal to 1 year and less than or equal to 30 years
             of age at initiation of protocol therapy.

          -  Diagnosis: Patients must have a confirmed histologic diagnosis of a relapsed or
             refractory solid tumor or CNS malignancy.

          -  Performance status: Patients over 16 years of age must have a Karnofsky score greater
             than or equal to 50. Children under 16 years of age must have a Lansky score greater
             than or equal to 50.

          -  Prior therapy: Patients may have received prior therapy with vincristine, irinotecan,
             or temozolomide. They may not however have received therapy that included a treatment
             cassette of irinotecan and temozolomide in combination.

               -  Prior myelosuppressive therapy: Patients must have not received myelosuppressive
                  therapy in 3 weeks or nitrosourea chemotherapy within 6 weeks of initiation of
                  protocol therapy.

               -  Hematologic growth factor support: Patients may not have received G-CSF within
                  the previous 3 days or peg-filgrastim within the past 7 days.

               -  Biologic anti-neoplastic therapy: At least 21 days or 5 half-lives (whichever is
                  of longer duration) must have elapsed since the last administration of biologic
                  antineoplastic therapy.

               -  Radiation therapy: ≥ 14 days since the last dose of local XRT; ≥ 6 months must
                  have elapsed if prior TBI, craniospinal XRT or ≥ 50% radiation of pelvis; ≥ 6 wks
                  must have elapsed if other substantial BM radiation.

               -  Autologous or allogeneic stem cell transplant: No active graft vs. host disease
                  or need for immunosuppressive therapy. At least 3 months must have passed since
                  neutrophil engraftment.

          -  Organ function:

        Bone marrow function:

          -  Peripheral absolute neutrophil count (ANC) greater than or equal to 1000 cells/mcL.

          -  Platelet count greater than or equal to100,000/mcL and no platelet transfusion within
             prior 7 days.

          -  Hemoglobin greater than or equal to 8 gm/dL

          -  Patients with known bone marrow metastatic disease may enroll on the study if they
             have a peripheral ANC greater than or equal to 750 cells/mcL. They will not be
             evaluable for hematologic toxicity.

             - Adequate liver function:

          -  Total bilirubin less than or equal to 1.5x upper limit of normal (ULN) for age.

          -  SGPT (ALT) less than or equal to 5x ULN

          -  Serum albumin greater than or equal to 2 gm/dL

             - Adequate renal function:

          -  Creatinine clearance or glomerular filtration rate >70 ml/min/1.73 m2 or a serum
             creatinine based on age and gender as follows:

        Age Maximum serum creatinine concentration (mg/dL) Male Female 1-<2 years 0.6 0.6 2-<6
        years 0.8 0.8 6-<10 years 1 1 10-<13 years 1.2 1.2 13-<16 years 1.5 1.4 greater than or
        equal to 16 years 1.7 1.4 The threshold creatinine values in this table were derived from
        the Schwartz formula to estimate glomerular filtration rates (Schwartz et al. J. Peds. 106;
        522. 1985) using child length and stature data from the CDC.

        - Informed consent: All patients less than 18 years of age must sign a written informed
        consent. For patients <18 years of age, a parent or guardian must sign a written informed
        consent, unless the patient is an emancipated minor. Childhood assent, when appropriate,
        should be obtained as well per institutional guidelines.

        Exclusion Criteria:

          -  Pregnancy or breast feeding: Women who are pregnant or breast feeding will not be
             entered on the protocol due to the risks of fetal and teratogenic adverse events with
             the therapeutic agents used in the protocol therapy.

          -  Corticosteroid use: Patients with CNS tumors who have not been on a stable or
             decreasing dose of corticosteroids for the 7 days prior to the initiation of protocol
             therapy.

          -  Antineoplastic therapy: Patients receiving any other antineoplastic therapy.

          -  Medication allergy:

        Allergy or intolerance to any of the protocol agents: vincristine, irinotecan,
        temozolomide, or vorinostat.

        Allergy or intolerance to cephalosporins.

          -  Infection: Patients who have any uncontrolled infection, positive blood culture within
             48 hours prior to protocol entry, or diagnosed or receiving therapy for Clostridium
             difficile infection.

          -  Patients may not have taken valproic acid or any other histone deacetylase inhibitor
             for at least 2 weeks prior to study enrollment.

          -  Children with neurofibromastosis Type 1, if being used for treatment of a low grade
             glioma.
      

Gender

All

Ages

1 Year - 30 Years

Accepts Healthy Volunteers

No

Contacts

Jeremy Rosenblum, MD, 914-594-2143, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT04308330

Organization ID

12011


Responsible Party

Sponsor

Study Sponsor

New York Medical College


Study Sponsor

Jeremy Rosenblum, MD, Principal Investigator, New York Medical College


Verification Date

February 2020