Study of Crenolanib in Recurrent/Refractory Glioblastoma With PDGFRA Gene Amplification

Phase II Study of Single-agent Crenolanib in Recurrent/Refractory Glioblastoma With PDGFRA Gene Amplification

This is a proof of concept, single-arm study to investigate crenolanib monotherapy in patients with recurrent/refractory glioblastoma with PDGFRA gene amplification by assessing the progression-free survival (PFS) at 6 months. Crenolanib will be given orally starting at 100 mg TID continuously until disease progression, unacceptable toxicity, or consent withdrawal.

Study Overview

• Status: Completed
• Conditions: Recurrent/Refractory Glioblastoma
• Intervention / Treatment: Drug: crenolanib

Detailed Description

This is a proof of concept, single-arm study to investigate crenolanib monotherapy in patients with recurrent/refractory glioblastoma with PDGFRA gene amplification. Eligible patients include those with recurrent/refractory glioblastoma after prior therapy including surgery, radiation, and temozolomide. The trial is designed to assess the anti-tumor activity of crenolanib in recurrent/refractory glioblastoma with PDGFRA gene amplification based on the estimation of progression-free survival (PFS) at 6 months. Symptom burden will be evaluated using the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT).

Crenolanib will be administered orally continuously at 100 mg TID on a 28-day cycle basis . Patients are allowed to receive crenolanib for a maximum of 26 cycles if clinical benefit has been observed.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 75243
      • Md Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients (male or female) ≥ 18 years of age.
2. Histopathologically confirmed glioblastoma or gliosarcoma (WHO Grade IV) confirmed by local pathology tissue screening.
3. Radiologic evidence of first recurrence after initial treatment (including surgery, radiation, and temozolomide) or tumor refractory to initial treatment without subsequent treatment in glioblastoma or gliosarcoma (WHO Grade IV). Transformation from a lower grade glioma previously treated with radiation and/or temozolomide to glioblastoma will be considered first recurrence for the purpose of this trial
4. Tumor tissue available from original diagnosis and/or recurrence; a minimum of 1 FFPE archival tumor tissue block (preferred) or a minimum of 20 FFPE unstained slides from initial and/or most recent pre-registration biopsy or resection. It is recommended that at least 1 cm^2 of tissue composed primarily (defined as greater than 85%) of tumor is present.
5. Confirmed PDGFRA amplification in the tumor tissue at the time of diagnosis or time of recurrence. Central confirmation of PDGFRA amplification will be performed by FISH in CLIA certified lab (ProPath). Signal quantitation will be used to generate a PDGFRA/centromere 4 ratio. PDGFRA to Centromere 4 ratios will be interpreted as follows: 1.8 to 2.2, borderline for amplification; 2.2 to 5.0, low-level amplification; and greater than 5.0 or clustered signals that are too numerous to count would be considered highly amplified. Tumor samples with PDGFRA to Centromere 4 ratios of 2.2 or higher will be considered amplified and therefore eligible for this trial. For patients with local CLIA testing demonstrating PDGFRA amplification by Next Generation Sequencing (Foundation Medicine, CMS400), central testing will not be required.

6. Patients must have adequate organ function at baseline as defined below:

   • Adequate liver function (within 7 days of crenolanib commencement), as determined by:

   • Serum ALT, AST ≤ 2 × ULN
   • Normal serum total bilirubin (lower and upper limits of local Laboratory)
   • Adequate renal function assessed by: serum creatinine ≤ 1.5 × ULN
7. KPS ≥ 60
8. Recovered (returned to ≤ grade 1 as per CTCAE v4.03) from prior treatment-related toxicity.
9. A minimum of 3 weeks must have elapsed from last intake of prior standard chemotherapy treatment.
10. A minimum of 6 weeks must have elapsed from the last dose of nitrosoureas.
11. A minimum of 5 half-lives of last dose of investigational agent must have elapsed prior to C1D1.
12. More than 12 weeks from completion of chemoradiation, unless RANO criteria for early progression within 12 weeks of chemoradiation are met (See 18.1)
13. Non-pregnant and non-nursing women of childbearing potential must have a negative serum or urine pregnancy test within 3 days of crenolanib commencement ("Women of childbearing potential" is defined as a sexually active mature woman who has not undergone a hysterectomy or who has had menses at any time in the preceding 24 consecutive months).
14. Women of childbearing potential and men must agree to use adequate contraception (simultaneous use of 2 methods of birth control) prior to study entry, for the duration of study participation and for 90 days following completion of therapy.
15. Patient able and willing to provide informed consent.
16. Ability to understand and willingness for follow-up visits.

Exclusion Criteria:

1. Pre-existing liver diseases (i.e., cirrhosis, chronic hepatitis B or C, nonalcoholic steatohepatitis, and sclerosing cholangitis, etc.)
2. Known positive for HIV
3. Patients previously treated with bevacizumab.
4. NYHA Class III-IV heart failure, myocardial infarction <6 months prior to study entry, and/or serious arrhythmia requiring anti-arrhythmic therapy
5. Patients receiving concurrent anti-cancer treatment (chemotherapy, investigational agents, immunotherapy, endocrine therapy, or Optune®…)
6. Patients with any other severe and/or uncontrolled concurrent disease affecting the cardiovascular system, liver, kidneys, hematopoietic system or else considered as clinically important by the investigator and that could be incompatible with patient's participation in this trial or would likely interfere with study procedures/results or compromise compliance with the protocol.
7. Pregnant or breast-feeding women.
8. Patients unable to swallow pills.
9. Patients who are allergic to MRI contrast medium or unable to undergo MRI for any other reason.
10. Patients unable to provide informed consent.
11. Patients on EIADs are not eligible, unless the antiepileptic drug can be safely tapered and discontinued before C1D1.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; crenolanib 100mg PO TID	Drug: crenolanib; single-agent crenolanib at 100 mg PO TID; Other Names: CP-868,596-26

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Progression-free survival at 6 months	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	3 years
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03	2 years
Overall response rate by RANO criteria	1 year
Change in symptom burden using The MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT)	2 years

Other Outcome Measures

Outcome Measure	Time Frame
Duration of response	2 years

Collaborators and Investigators

• Sponsor: Arog Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Barbara O'Brien, MD, M.D. Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): July 1, 2020
• Study Completion (Actual): July 1, 2020

Study Registration Dates

• First Submitted: November 3, 2015
• First Submitted That Met QC Criteria: December 8, 2015
• First Posted (Estimate): December 10, 2015

Study Record Updates

• Last Update Posted (Actual): July 20, 2020
• Last Update Submitted That Met QC Criteria: July 17, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Disease Attributes; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Recurrence; Antineoplastic Agents; Crenolanib
• Other Study ID Numbers: ARO-015

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO