Study of Dasatinib in Combination With Everolimus for Children and Young Adults With Gliomas Harboring Platelet-Derived Growth Factor Receptor (PDGFR) Alterations

NCT03352427 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: UMCC 2017.042HUM00123094
• Study Type: interventional
• Target: 3
• Locations: 1 country
• Sites: 1

Brief Summary

This trial will evaluate the activity of dasatinib in combination with everolimus for children with gliomas harboring PDGFR alterations, including newly diagnosed high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG) after radiation (stratum A); and recurrent/progressive glioma (grade II-IV, including DIPG) (stratum B).

Conditions

Glioma; High Grade Glioma; Pontine Tumors

Outcome Measures

Primary Outcomes (3)

• Progression-free Survival in Participants With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)

  Percentage of participants without progression, defined as 25% increase in the size of the tumor or appearance of new lesions.

  8 months

• Progression-free Survival in Participants With Newly Diagnosed High-grade Glioma (HGG)

  Percentage of participants without progression, defined as 25% increase in the size of the tumor or appearance of new lesions.

  12 months

• Overall Response Rate (OR) (Partial Response or Better) in Participants With Refractory or Recurrent Glioma

  The overall response assessment will take into account response in both target and non-target lesions, as well as the appearance of new lesions. Partial Response (PR) will be defined as ≥50% decrease in size of tumor in comparison to baseline measurements. Complete Response (CR) will be defined as the disappearance of all abnormal signal. This includes return to normal size of the brain stem for brain stem lesions. Reported as percentage of participants with partial or better response at 56 days.

  56 Days

Secondary Outcomes (2)

• Overall Survival

  1 year

• Overall Survival

  up to 17 months

Study Arms (1)

Dasatinib+Everolimus

EXPERIMENTAL

Dasatinib = 60 mg/m2 orally twice daily Everolimus = starting dose of 3.0 mg/m2, with titration of dosing after first cycle to keep everolimus trough level of 5-15 ug/ml Both agents will be taken daily for 28 day cycles. Cycles will be repeated every 28 days and patients may receive up to 24 cycles.

Drug: Dasatinib; Drug: Everolimus

Interventions

Dasatinib DRUG

60 mg/m2 orally twice daily

Dasatinib+Everolimus

Everolimus DRUG

3.0 mg/m2, with titration of dosing after first cycle to keep trough level of 5-15 ug/ml

Dasatinib+Everolimus

Eligibility Criteria

• Age: 1 Year - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Histological confirmation of a newly diagnosed high-grade glioma or diffuse intrinsic pontine glioma (DIPG) (Stratum A)
• Histological confirmation (at diagnosis or relapse) of a recurrent or progressive grade II-IV glioma (including DIPG) (Stratum B)
• Participants must have a genomic (DNA and/or RNA) alteration (mutation, fusion, and/or amplification) involving PDGF-A, PDGF-B, PDGFR-A or PDGFR-B, as identified by tumor sequencing.
• Age at enrollment: Greater than 1 year and less than 50 years
• BSA (body surface area): BSA greater than 0.3 m2
• Karnofsky (Measure of performance for cancer patients where 100% represents perfect health) \> 50% for patients \> 16 years of age and Lansky (Measure of performance for pediatric cancer patients where 100% represents perfect health) \> 50% for patients \< 16 years of age. Neurologic deficits in patients with CNS tumors must have been relatively stable for a minimum of 7 days. Patients who are unable to walk because of paralysis, but who are able to sit in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
• Adequate bone marrow function per protocol
• Adequate liver function per protocol
• Adequate renal and metabolic function per protocol
• Patients with known seizure disorder must have seizures adequately controlled with non- enzyme inducing antiepileptic medications
• No increase in steroid dose within the past 7 days
• Primary brain or spine tumor are eligible, including tumors with metastases, multiple lesions.
• Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy.
• Myelosuppressive chemotherapy: Must not have received within 3 weeks.
• Hematopoietic growth factors: At least 7 days since the completion of therapy with a growth factor, 14 days for long- acting.

You may not qualify if:

• Patients who are breastfeeding, pregnant or refuse to use an effective form of birth control are excluded.
• Patients with uncontrolled infection are excluded.
• Patients receiving other anti-neoplastic agents are excluded.
• Patients requiring strong CYP3A4 or PGP inhibitors are excluded (per protocol)
• Patients requiring anticoagulation or with uncontrolled bleeding are excluded.
• Patients on steroids for symptom management must be on a stable dose for 7 days prior to start of treatment.
• Patients within 1 year of allogeneic stem cell transplant, patients with active GVHD or requiring immunosuppression are excluded.
• Previous hypersensitivity to rapamycin or rapamycin derivatives

Sponsors & Collaborators

• University of Michigan Rogel Cancer Center: lead

Study Sites (1)

University of Michigan Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Related Publications (1)

• Miklja Z, Yadav VN, Cartaxo RT, Siada R, Thomas CC, Cummings JR, Mullan B, Stallard S, Paul A, Bruzek AK, Wierzbicki K, Yang T, Garcia T, Wolfe I, Leonard M, Robertson PL, Garton HJ, Wahl DR, Parmar H, Sarkaria JN, Kline C, Mueller S, Nicolaides T, Glasser C, Leary SE, Venneti S, Kumar-Sinha C, Chinnaiyan AM, Mody R, Pai MP, Phoenix TN, Marini BL, Koschmann C. Everolimus improves the efficacy of dasatinib in PDGFRalpha-driven glioma. J Clin Invest. 2020 Oct 1;130(10):5313-5325. doi: 10.1172/JCI133310.

  PMID: 32603316 RESULT

MeSH Terms

Conditions

Glioma; Brain Stem Neoplasms

Interventions

Dasatinib; Everolimus

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Sirolimus; Macrolides; Lactones

Limitations and Caveats

Trial enrollment was limited due to requirement for patient insurance coverage for all aspects of treatment. Due to limited sample size, full statistical analysis isn't possible. Descriptive results of this cohort compiled with data available from patients treated locally with a similar treatment plan is available in the following publication: Miklja et al, JCI, 2020 \[PMID: 32603316\].

Results Point of Contact

• Title: Carl Koschmann, MD
• Organization: University of Michigan

ckoschma@umich.edu

734-615-2736

Study Officials

• Carl Koschmann, M.D.

  University of Michigan Rogel Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2017
• First Posted: November 24, 2017
• Study Start: December 6, 2017
• Primary Completion: April 17, 2019
• Study Completion: May 15, 2019
• Last Updated: October 5, 2022
• Results First Posted: October 5, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)