Clinical trial NCT03352427: Study of Dasatinib in Combination With Everolimus for Children and Young Adults With Gliomas Harboring Platelet-Derived Growth Factor Receptor (PDGFR) Alterations
Official title: A Phase 2 Study of Dasatinib in Combination With Everolimus for Children With Gliomas Harboring PDGFR Alterations
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Glioma
High Grade Glioma
Pontine Tumors
Lead sponsor: University of Michigan Rogel Cancer Center
Sponsor class: OTHER
First posted: 2017-11-24
Enrollment: 3
Sex: ALL
Minimum age (years): 1
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


Eligibility criteria: Inclusion Criteria:

* 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.
* Biologic (anti-neoplastic agent): At least 7 days or 3 half-lives (whichever is longer) since the completion of therapy.
* Radiation therapy:

  * Stratum A: ≥ 2 weeks and \</= to 12 weeks must have elapsed from radiation.
  * Stratum B: ≥ 2 weeks must have elapsed from focal radiation.
* \> 3 weeks from major surgery. If recent craniotomy, adequate wound healing must be determined by neurosurgical team.
* Autologous Stem Cell Transplant or Rescue: No evidence of active graft vs. host disease and ≥ 4 weeks must have elapsed.
* All patients and/or a legal guardian must sign institutionally approved written informed consent and assent documents.

Exclusion Criteria:

* 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

Primary outcomes:
measure: Progression-free Survival in Participants With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG)
timeFrame: 8 months
measure: Progression-free Survival in Participants With Newly Diagnosed High-grade Glioma (HGG)
timeFrame: 12 months
measure: Overall Response Rate (OR) (Partial Response or Better) in Participants With Refractory or Recurrent Glioma
timeFrame: 56 Days
Secondary outcomes:
measure: Overall Survival
timeFrame: 1 year
measure: Overall Survival
timeFrame: up to 17 months
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan Cancer Center
state: Michigan
Study officials:
affiliation: University of Michigan Rogel Cancer Center
name: Carl Koschmann, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.