Cabozantinib With Topotecan-Cyclophosphamide

  • STATUS
    Recruiting
  • End date
    Dec 31, 2022
  • participants needed
    16
  • sponsor
    Dana-Farber Cancer Institute
Updated on 7 October 2021

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.

Description

This is a prospective, open-label, single arm, phase 1 clinical trial. A single cohort of patients with relapsed or refractory Ewing sarcoma or osteosarcoma will be enrolled and treated in a 3+3 design with a combination of cabozantinib, topotecan and cyclophosphamide.

The research study procedures include screening for eligibility and study treatment including medical tests and follow up visits.

  • 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.

It is expected that up to 16 people will take part in this research study.

This research study is a Phase I clinical trial, which tests the safety of an investigational drug combination and also tries to define the appropriate doses of the drugs to use for further studies. "Investigational" means that the drug combination is being studied.

The FDA (the U.S. Food and Drug Administration) has approved all medications included in this trial as a treatment for multiple types of cancers.

The combination of topotecan and cyclophosphamide has been used for treatment of this population. Cabozantinib has been used alone for treatment of Ewing sarcoma and osteosarcoma and shown to have an effect in some patients. This is the first time that cabozantinib will be studied in combination with topotecan and cyclophosphamide.

Details
Condition Refractory Ewing Sarcoma, Recurrent Osteosarcoma, Relapsed Osteosarcoma, Refractory Osteosarcoma, Relapsed Ewing Sarcoma
Treatment cyclophosphamide, Topotecan, Cabozantinib, Myeloid Growth Factor
Clinical Study IdentifierNCT04661852
SponsorDana-Farber Cancer Institute
Last Modified on7 October 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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
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
days after local palliative XRT (small port)
days after craniospinal XRT or if >50% radiation of pelvis
days after other substantial bone marrow radiation, including radionuclide therapy
Small molecule biologic therapy
days following the last dose of a small molecule biologic agent
\--- For agents with known adverse events occurring beyond 7 days, this
duration must be extended beyond the time in which adverse events are known to
occur and this should be discussed and approved by the overall PI
Prior use of cabozantinib is not allowed
Prior use of tyrosine kinase inhibitors (TKI), other than cabozantinib, is allowed
Monoclonal antibody: 21 days must have elapsed after the last dose of antibody
Myeloid growth factors
days following the last dose of long-acting growth factor (e.g., pegfilgrastim)
days following short-acting growth factor (e.g., filgrastim)
Immunotherapy: 4 weeks since the completion of immunotherapy (e.g. tumor vaccines) aside from monoclonal antibodies with immune effects
Cellular therapies (e.g. CAR-T, NK or autologous stem cell boost): 42 days must have elapsed after cellular therapy
Wound healing & surgery
Patients with unhealed and/or chronic wounds are not eligible
Patients with unhealed fractures are not eligible
Patients must be 2 weeks from prior major surgical procedure
Note: Biopsy and central line placement/removal are not considered major surgery
Participants must have normal organ function as defined below
Hematologic requirements for subjects without known bone marrow involvement by
disease
Absolute neutrophil count >1000/uL
Platelets 100,000/uL and transfusion independent, defined as not receiving a platelet transfusion for at least 7 days prior to CBC documenting eligibility
Hematologic requirements for subjects with bone marrow involvement by disease as demonstrated on clinically-indicated bone marrow biopsy
Absolute neutrophil count >750/uL
Platelets 50,000/uL and transfusion independent, defined as not receiving a platelet transfusion for at least 7 days prior to CBC documenting eligibility
Not known to be refractory to platelet or red cell transfusions
Hepatic Function
Total bilirubin 1.5 x upper limit of normal (ULN) for age (Patients with Gilbert's syndrome with a total bilirubin < 2 x ULN for age and a direct bilirubin within normal limits are permitted
ALT (SGPT) 135 U/L. For the purpose of this study, the ULN for ALT is 45 U/L
AST 90 U/L. For the purpose of this study, the ULN for AST is 40 U/L
Serum albumin > 2 g/dL
Renal Function
Serum creatinine based on age/sex as follows: Maximum Serum Creatinine (mg/dL)
Age 6 to < 10 years Male: 1 Female: 1
Age 10 to < 13 years Male: 1.2 Female1.2
Age 13 to < 16 years Male: 1.5 Female:1.4
Age 16 years Male: 1.7 Female: 1.4
OR Creatinine clearance 60 mL/min/1.73 m2 as obtained by nuclear medicine GFR testing for participants with creatinine levels greater than the above age/sex maximum allowed values
Proteinuria: Urinalysis with urine protein < 1+ or < 1.0g/24hrs on 24-hour urine collection analysis
Adequate Cardiac Function
No history of congenital prolonged QTc syndrome, NYHA Class III or IV congestive heart failure (CHF)
No clinically significant cardiac arrhythmias, stroke or myocardial infarction within 6 months prior to enrollment
QTc 480 msec. Note: Patients with Grade 1 prolonged QTc (450-480 msec) at the time of study enrollment should have correctable causes of prolonged QTc addressed if possible (i.e., electrolytes, medications)
Shortening fraction of > 27% or ejection fraction of > 50% (while not receiving medications for cardiac function)
Adequate Blood Pressure (BP) Control, defined as
For patients < 18 years old, 95th percentile for age, height and sex
For patients 18 years old, 140/90 mmHg
BP should be measured as and patients should not be receiving medication for treatment of hypertension
Central Nervous System Function, defined as: Patients with a known seizure disorder who are receiving non-enzyme inducing anticonvulsants and have well-controlled seizures may be enrolled
Adequate Coagulation, defined as: INR 1.5
Adequate Pancreatic Function, defined as: Serum lipase 1.5 x ULN
Ability to understand and/or the willingness of the patient (or parent or legally authorized representative, if minor) to provide informed consent, using an institutionally approved informed consent procedure

Exclusion Criteria

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
Current evidence of active bleeding, intratumoral hemorrhage or bleeding diathesis
Within 6 months prior to study enrollment, having history of pulmonary embolism, DVT, or other venous thromboembolic event
Within 6 months prior to study enrollment, having history of significant GI bleeding, GI perforation, intra-abdominal abscess or fistula
Within 6 weeks prior to study enrollment, having history of hemoptysis
Within 28 days prior to study enrollment, having history of significant traumatic brain injury
Patients who are unable to swallow intact tablets 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
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