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Cabozantinib in Combination With 13-cis-Retinoic Acid in Children With Relapsed or Refractory Solid Tumors

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ClinicalTrials.gov Identifier: NCT03611595
Recruitment Status : Not yet recruiting
First Posted : August 2, 2018
Last Update Posted : August 6, 2018
Sponsor:
Collaborator:
Exelixis
Information provided by (Responsible Party):
Peter Zage, University of California, San Diego

Brief Summary:
This study is being conducted in order to determine the safety, dose-limiting toxicities, and maximum tolerated dose of cabozantinib in combination with 13-cis-retinoic acid in patients with relapsed or refractory solid tumors including tumors of the central nervous system (CNS)

Condition or disease Intervention/treatment Phase
Solid Tumor Drug: Cabozantinib Drug: 13-cis-retinoic acid Phase 1

Detailed Description:

Participants will be treated in an open-label, non-randomized phase I trial to determine the safety, dose-limiting toxicities, tolerability, and maximum tolerated dose of cabozantinib combined with 13-cis-retinoic acid in children with relapsed or refractory solid tumors.

Eligible Participants must have a histologically confirmed solid tumor at time of initial diagnosis, and have either progressive, recurrent, or refractory disease. Cabozantinib will be given orally once every day with cycles repeated every 4 weeks (28 days, +/- 3 days), with no rest periods between cycles, combined with 13-cis-retinoic acid at 80mg/m2/dose twice daily for two consecutive weeks (14 days) out of every four weeks (28 days, +/- 3 days). Participants with disease response or stable disease at the end of each cycle will be allowed to continue treatment, and patients may continue to receive therapy until there is evidence of clinical or radiographic disease progression.

The investigator will perform a phase I trial to define the maximum tolerated dose (MTD) of cabozantinib in combination with 13-cis-retinoic acid using the standard 3+3 study design. Cohorts of patients will be enrolled at doses determined as detailed below. The first cycle will be used to determine the dose-limiting toxicities. Toxicity will be summarized by dose levels. Response rates will be estimated. Kaplan-Meier curves will be plotted to graphically present time to progression (PFS) and other time-to-event endpoints. Median PFS and the corresponding 95% confidence intervals will be reported.

Cabozantinib dosing will be started and modified, if necessary, during the course of the trial as detailed below. The tablet formulation of the drug will be used with doses in 20mg increments.

Baseline evaluation to determine eligibility will include medical history (including a review of current medications), physical examination, blood count with differential, chemistry panel blood or urine pregnancy test for women of child-bearing potential (not post-menopausal for at least 12 months and not surgically sterile), echocardiogram, electrocardiogram, and disease evaluation (appropriate for disease). Samples for correlative studies will be collected accordingly.

Participants will be evaluated weekly (+/- three days) during the first cycle. The interim evaluations will consist of interval history (with a review of current medications), physical examination, blood count with differential, and chemistry panel. Pregnancy tests will be performed prior to each cycle in women of childbearing potential. After the first cycle, patients will be evaluated monthly (+/- seven days).

Participants who have had therapy discontinued will undergo end-of-therapy evaluations and will continue to be monitored with interval histories, physical examinations, and laboratory evaluations every three months (+/- seven days), with disease evaluations every three months (+/- 28 days) until they fulfill criteria for removal from study or the study is completed


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A National Phase I Study of Cabozantinib in Combination With 13-cis-Retinoic Acid in Children With Relapsed or Refractory Solid Tumors
Estimated Study Start Date : September 2018
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : September 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cabozantinib and 13-cis-retinoic acid
Cabozantinib will be given orally once every day with cycles repeated every 4 weeks (28 days, +/- 3 days), with no rest periods between cycles, combined with 13-cis-retinoic acid at 80mg/m2/dose twice daily for two consecutive weeks (14 days) out of every four weeks (28 days, +/- 3 days).
Drug: Cabozantinib
Cabozantinib will be given orally once every day with cycles repeated every 4 weeks (28 days, +/- 3 days), with no rest periods between cycles
Other Name: CABOMETYX

Drug: 13-cis-retinoic acid
13-cis-retinoic acid at 80mg/m2/dose twice daily for two consecutive weeks (14 days) out of every four weeks (28 days, +/- 3 days).
Other Name: isotretinoin




Primary Outcome Measures :
  1. maximum tolerated dose of cabozantinib plus 13-cis-retinoic acid [ Time Frame: 12 months ]
    We will employ the 3+3 design to find the maximum tolerated dose (MTD) of cabozantinib when used in combination with 13-cis-retinoic acid



Information from the National Library of Medicine

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Ages Eligible for Study:   2 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients must have had histologic verification of a solid tumor, including tumors of the CNS, at the time of initial diagnosis or relapse, with disease that has progressed on standard therapy, relapsed after standard therapy, or for which no standard curative therapy is known
  2. Patients must have documentation of either measurable or evaluable disease within 4 weeks of onset of study therapy
  3. Performance Status - Lansky play or Karnofsky score of ≥40
  4. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to study enrolment with the exception of hematologic parameters (absolute neutrophil count, hemoglobin, platelet count), which need to have recovered to meet eligibility criteria

5 Steroids are permitted for control of emesis and for symptom management in patients with intracranial metastases. However, patients with known CNS disease or CNS metastases who require increasing doses of steroids are not allowed in the study. Patients MUST be on a stable or decreasing steroid dose for greater than or equal to 1 week prior to start of study therapy.

6. Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used

Exclusion Criteria:

  1. Evidence of severe or uncontrolled systemic disease, or any concurrent condition which in the Investigator's opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol.
  2. Cardiac Disease:
  3. Blood pressure >95th percentile for age (either systolic or diastolic) or >140/90 for patients >18 years of age and uncontrolled by oral medication at onset of study therapy
  4. Women who are currently pregnant or breastfeeding.
  5. Prior therapy with cabozantinib at any time.
  6. Major surgery within 8 weeks before starting study therapy.
  7. Prior treatment with allogeneic stem cell transplantation or total body irradiation (TBI)
  8. Therapeutic anticoagulation with heparins, LMWH , or any other agents are not allowed in subjects with intracranial tumors/metastatses.
  9. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel) in patients without primary or metastatic CNS tumors
  10. The subject has experienced any of the following:

    1. clinically-significant GI bleeding within 6 months before the first dose of study treatment;
    2. any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.
  11. The subject has radiographic evidence of cavitating pulmonary lesion(s) and/or the subject has tumor invading any major blood vessels;
  12. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib
  13. thromboembolic event requiring therapeutic anticoagulation within 6 months of onset of study treatment (Note: subjects with a venous filter (eg, vena cava filter) are not eligible for this study).
  14. GI disorders particularly those associated with a high risk of perforation or fistula formation
  15. Inability to swallow intact tablets
  16. Previously identified allergy or hypersensitivity to components of the study treatment formulations
  17. The subject requires chronic concomitant treatment with strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's Wort).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03611595


Contacts
Contact: Peter Zage, MD 858-534-6494 pzage@ucsd.edu

Locations
United States, California
UC San Diego Moores Cancer Center
La Jolla, California, United States, 92093
Sponsors and Collaborators
Peter Zage
Exelixis
Investigators
Principal Investigator: Peter Zage University of California, San Diego

Responsible Party: Peter Zage, Associate Professor-in-Residence, University of California, San Diego
ClinicalTrials.gov Identifier: NCT03611595     History of Changes
Other Study ID Numbers: 171971
First Posted: August 2, 2018    Key Record Dates
Last Update Posted: August 6, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Peter Zage, University of California, San Diego:
13-cis-Retinoic Acid
Children
Relapsed Solid Tumors
Refractory Solid Tumors
Solid Tumors
cancer

Additional relevant MeSH terms:
Neoplasms
Tretinoin
Isotretinoin
Antineoplastic Agents
Keratolytic Agents
Dermatologic Agents