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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Recurrent/Refractory Glioblastoma	Drug: crenolanib	Phase 2

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	33 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Phase II Study of Single-agent Crenolanib in Recurrent/Refractory Glioblastoma With PDGFRA Gene Amplification
Study Start Date :	April 2016
Estimated Primary Completion Date :	April 2020
Estimated Study Completion Date :	April 2020

Arms and Interventions

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

Outcome Measures

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Primary Outcome Measures :

1. Progression-free survival at 6 months [ Time Frame: 6 months ]

Secondary Outcome Measures :

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

Other Outcome Measures:

1. Duration of response [ Time Frame: 2 years ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Contacts

Contact: Hyuntae Yoo, Ph.D.	214-593-0527	hyoo@davacro.com

Locations

United States, Texas
MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 75243
Contact: Marta Penas-Prado, M.D.

Sponsors and Collaborators

Arog Pharmaceuticals, Inc.

Investigators

Principal Investigator:	Barbara O'Brien, MD	M.D. Anderson Cancer Center

More Information

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Responsible Party:	Arog Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier:	NCT02626364 History of Changes
Other Study ID Numbers:	ARO-015
First Posted:	December 10, 2015
Last Update Posted:	January 10, 2019
Last Verified:	January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Additional relevant MeSH terms:

Glioblastoma; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal	Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Crenolanib; Antineoplastic Agents