Cabozantinib With Topotecan-Cyclophosphamide

NCT04661852 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 20-535
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

Brief Summary

This research study is a clinical trial of a new combination of drugs as a possible treatment for relapsed/refractory Ewing sarcoma and/or osteosarcoma.

• The names of the drugs are:
• Cabozantinib
• Topotecan
• Cyclophosphamide
• The names of the non-investigational supportive care drugs are:
• Filgrastim, pegfilgrastim, or a related growth factor.

Conditions

Relapsed Ewing Sarcoma; Refractory Ewing Sarcoma; Relapsed Osteosarcoma; Refractory Osteosarcoma

Keywords

Relapsed Ewing Sarcoma; Refractory Ewing Sarcoma; Relapsed Osteosarcoma; Refractory Osteosarcoma

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerate Dose

  Combination of cabozantinib with cyclophosphamide and topotecan * If no Dose Limiting Toxicities occur during the first cycle for all three subjects, dose escalation to the next highest dose level will occur for the next three enrolling patients. * If one out of three patients experience a DLT during the first cycle of therapy, up to three additional subjects will then be enrolled at the same dose level for a total of six patients at this dose level. If two or more patients experience DLTs in the 1st cycle, the trial will stop enrollment and this dose level will be the MAD. * Up to six additional patients will be enrolled at the dose level below the MAD, with the MTD being established once ≤1 patient in a dose level experiences DLTs. * If two out of three patients experience DLTs during the 1st cycle, the protocol will halt enrollment at this dose level, which will be considered the MAD.

  1 Year

Secondary Outcomes (3)

• Number of Participants with Treatment Related Adverse Events as Assessed by CTCAE v5.0

  1 year

• Objective Response Rate

  1 year

• Progression Free Survival

  study entry to first episode of disease progression or death, with patients without these events censored at last follow-up up to 1 year

Study Arms (1)

CABOZANTINIB WITH TOPOTECAN-CYCLOPHOSPHAMIDE

EXPERIMENTAL

Participants will be accrued to dose levels in cohorts of 3 using the 3 + 3 design with a combination of cabozantinib, topotecan and cyclophosphamide. * Each study treatment cycle lasts 21 days. * Participants may receive up to 17 cycles. * Participants will be assigned a specific dose and schedule of the study drugs determined when enrolled in the study.

Drug: Cabozantinib; Drug: Topotecan; Drug: Cyclophosphamide; Drug: Myeloid growth factor

Interventions

Cabozantinib DRUG

PO (dose and schedule based upon dose level and nomogram)

Also known as: COMETRIQ™

CABOZANTINIB WITH TOPOTECAN-CYCLOPHOSPHAMIDE

Topotecan DRUG

IV, over 30 minutes (schedule based upon dose level)

Also known as: Hycamtin®

CABOZANTINIB WITH TOPOTECAN-CYCLOPHOSPHAMIDE

Cyclophosphamide DRUG

IV, over 30 minutes (schedule based upon dose level)

Also known as: Neosar®, Cytoxan®

CABOZANTINIB WITH TOPOTECAN-CYCLOPHOSPHAMIDE

Myeloid growth factor DRUG

subcutaneous filgrastim (daily until ANC ≥ 1,500/mm3 after nadir) or pegfilgrastim (once) must be given, with choice of agent per institutional standard or treating physician preference, starting on day 5, 6, 7 or 8 (depending upon chemotherapy timing)

Also known as: Filgrastim, Pegfilgrastim

CABOZANTINIB WITH TOPOTECAN-CYCLOPHOSPHAMIDE

Eligibility Criteria

• Age: 6 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age ≥ 6 years and ≤ 30 years at time of enrollment. Note the requirement to swallow intact pills and BSA requirement immediately following.
• BSA ≥1.25m2 and \<2m2 is required.
• Patients with BSA \< 1.25m2 are not eligible for enrollment due to percent deviation of daily cabozantinib dose being too extreme as a result of limitations in the size of dose forms available.
• Patients with BSA \>2m2 are not eligible for enrollment due to inability to provide sufficient dose escalation and de-escalation for cabozantinib due to restraints imposed by dose of individual pills.
• Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥ 50% for patients \<16 years of age
• Disease Requirement: Participants must have relapsed or refractory Ewing sarcoma or osteosarcoma as follows:
• For osteosarcoma, disease must be designated as a high-grade lesion (HGOS). Diagnosis of low-grade osteosarcoma (LGOS) and parosteal osteosarcoma (POS) are excluded.
• Histologic diagnosis consistent with Ewing sarcoma or PNET with molecular evidence of translocation involving EWSR1 or FUS (also known as TLS), such as FISH, RT-PCR, or next generation sequencing. If the translocation partner is known, it must be of the ETS family (e.g.. FLI1 or ERG). For patients referred to the study center from outside institutions, the local institutional analysis of prior tumor material may serve to fulfill this requirement.
• Patients must have fully recovered (Common Terminology Criteria for Adverse Events \[CTCAE\] version 5 Grade ≤1) from the acute toxic effects of all prior anti-cancer therapy except organ function. Patients must meet the following minimum washout periods prior to enrollment:
• Myelosuppressive chemotherapy
• ≥ 14 days since the last dose of myelosuppressive chemotherapy (≥ 42 days since the last dose of nitrosourea or mitomycin C);
• Prior use of topotecan or cyclophosphamide is permitted. Patients treated with the combination of topotecan and cyclophosphamide must meet these additional criteria:
• No progression on the combination of topotecan/cyclophosphamide.
• If topotecan/cyclophosphamide is the regimen immediately preceding enrollment to this trial, then no more than two prior cycles prior to transitioning to this trial.
• Radiotherapy

You may not qualify if:

• Prior solid organ or allogeneic hematopoietic cell transplantation.
• Patients with primary or metastatic CNS Ewing sarcoma or osteosarcoma except patients with a history of CNS metastatic disease that has been resected and/or radiated without evidence of active CNS disease for 3 months preceding enrollment.
• Prohibited Concomitant Medications
• Corticosteroids: Patients requiring corticosteroids who have not been on a stable or decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible. If used to modify immune adverse events related to prior therapy, ≥ 14 days must have elapsed since last dose of corticosteroid.
• Anti-hypertensive Medications: Patients who are currently receiving any maintenance or PRN anti-hypertensive medication are not eligible for study enrollment.
• Investigational Drugs: Patients who are currently receiving an investigational drug are not eligible.
• Concomitant anticoagulation with anticoagulants (e.g., warfarin, direct thrombin, Factor Xa inhibitors, heparins) or platelet inhibitors (e.g., clopidogrel, aspirin) is prohibited.
• CYP3A4 active agents: specific CYP3A inducers and inhibitors, including enzyme-inducing anticonvulsants, are prohibited and are listed in Appendix B. They must not be taken within 7 days of starting cabozantinib.
• QT prolonging agents: specific QT prolonging agents are prohibited. They must not be taken at the time of enrollment.
• Pregnant participants will not be entered on this study given that the effects of cabozantinib on the developing human fetus are unknown. Female participants of childbearing potential must have a documented negative pregnancy test during screening.
• Breastfeeding mothers are not eligible due to unknown risk for adverse events in nursing infants secondary to treatment of the mother with cabozantinib.
• Intercurrent illness including, but not limited to, ongoing/persistent infection (fevers \>38.5 for ≥ 5 days), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients with a known history of HIV and/or hepatitis B (testing not required as part of screening).
• Patients with gastrointestinal disease or disorder that could interfere with absorption of cabozantinib such as bowel obstruction or inflammatory bowel disease.
• Bleeding or thrombosis:

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead

Study Sites (2)

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

MeSH Terms

Conditions

Sarcoma, Ewing; Osteosarcoma

Interventions

cabozantinib; Topotecan; Cyclophosphamide; Granulocyte Colony-Stimulating Factor; Filgrastim; pegfilgrastim

Condition Hierarchy (Ancestors)

Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Officials

• Steven C DuBois, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 4, 2020
• First Posted: December 10, 2020
• Study Start: December 23, 2020
• Primary Completion: October 24, 2022
• Study Completion: October 24, 2022
• Last Updated: February 15, 2023

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu

Locations

US (2)