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Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions, Including the D842V Mutation, in the PDGFRA Gene


Phase 2
18 Years
N/A
Open (Enrolling)
Both
D842-related Mutant GIST

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Trial Information

Phase II Study of Crenolanib (CP-868,596), a Selective and Potent Inhibitor of PDGFR, for the Treatment of Patients With Advanced Gastrointestinal Stromal Tumors With the D842-related Mutations and Deletions, Including the D842V Mutation, in the PDGFRA Gene


Crenolanib (CP-868,596) is an orally bioavailable, selective inhibitor of PDGFR receptor
tyrosine kinase with IC50s of 0.4 ng/mL and 0.8 ng/mL for PDGFRα and PDGFRβ, respectively.

In preclinical models of cell lines with the D842V mutation in the PDGFRA gene, crenolanib
(CP-868,596) blocked phosphorylation of PDGFRα at nanomolar concentrations, suggesting that
it may provide a clinical benefit to patients with D842V mutant GIST.

In addition, crenolanib was also active in inhibiting phosphorylation of cell lines with two
point mutations (double mutants) PDGFRA V561D + D842V and PDGFRA T674I + D842V.

Inclusion Criteria


Inclusion Criteria

- Male or female, of any racial or ethnic group

- Age 18 years or older

- Life expectancy of greater than 12 weeks

- Patient able and willing to provide informed consent

- Normal liver function, defined as AST and ALT ≤2.5x ULN, and Total Bilirubin ≤ 2x
ULN.

- Total creatinine ≤ 1.5x ULN

- ECOG Performance Status 0 - 2 (Appendix II)

- Patients must have histologically or cytologically confirmed GIST with a D842-related
mutation or deletion on the PDGFRA gene

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as
>20 mm with conventional techniques or as >10 mm with spiral CT scan. See Section
10.1.2 for the evaluation of measurable disease.

- Patients must have recovered from any prior therapy and completed the minimum of,
either 5 half-lives of prior therapy or 2 weeks must have elapsed since prior
treatment

Exclusion Criteria

- Patient unable to provide informed consent

- ECOG Performance status > 2

- Any concurrent anticancer therapy, immunotherapy, or hormonal therapy.

- Any other investigational agents taken within 2 weeks of start of study drug or if
study drug will commence within 5 half-lives of prior therapy

- Patients with known or active Hepatitis B or C; liver cirrhosis.

- Patients with active fungal, viral, and bacterial infections

- Positive serum pregnancy test

- Pregnant or lactating women

- Patients on concomitant medications that induce or inhibit CYP3A4 (Appendix III)

- Patients with severe and/or uncontrolled concurrent medical disease that in the
opinion of the investigator could cause unacceptable safety risks or compromise
compliance with the protocol e.g. impairment of gastrointestinal (GI) function, or GI
disease that may significantly alter the absorption of the study drugs

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

The primary end-point is overall response rate

Outcome Description:

To determine the response rate of patients with advanced D842V mutant GIST, when treated with Crenolanib (CP-868,596). Response will primarily be determined by RECIST criteria

Outcome Time Frame:

1.5 years

Safety Issue:

No

Principal Investigator

Margaret von Mehren, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Fox Chase Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

ARO-BRE-002

NCT ID:

NCT01243346

Start Date:

April 2011

Completion Date:

September 2014

Related Keywords:

  • D842-related Mutant GIST
  • Gastrointestinal Stromal Tumor
  • PDGFR Inhibitor
  • Crenolanib (CP-868,596)
  • Gastrointestinal Stromal Tumors

Name

Location

Fox Chase Cancer CenterPhiladelphia, Pennsylvania  19111
Knight Cancer Institute, Oregon Health and Science UniversityPortland, Oregon  97239-3098