Phase II Trial of the Gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors/Aggressive Fibromatosis

NCT01981551 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 14000714-C-0007
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 1

Brief Summary

Background:

• Desmoid tumors (also known as aggressive fibromatosis), are rare, locally invasive, slow-growing soft-tissue tumors. The disease can be either asymptomatic or be associated with severe loss of organ function and significant morbidity.
• Treatment with the selective small-molecule Gamma-secretase inhibitor PF-03084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early phase clinical trial.
• The Notch pathway is a key regulator of cell differentiation, proliferation and apoptosis; aberrant signaling via the Notch pathway is associated with carcinogenesis. Objectives:
• Primary: Determine the response rate (Complete Response (CR)+Partial Response (PR)) of PF-03084014 in patients with desmoid tumors/aggressive fibromatosis
• Secondary: Assess symptom measures at baseline and on study; perform genotyping for germline and somatic mutations in adenomatous polyposis coli gene (APC) and catenin-beta 1 (CTNNB1) genes; correlate clinical response to therapy with genotyping data; and assess modulation of the Notch pathway by evaluating notch response genes in tumor biopsies at baseline and after drug administration Eligibility:
• Age greater than or equal to18; histologically confirmed desmoid tumor not amenable to curative resection or definitive radiation therapy that has progressed after receiving at least one line of standard treatment; adequate organ function
• Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies Study Design:
• This is an open-label Phase II trial of PF-03084014; study drug will be administered orally at 150 mg twice a day in 21-day cycles
• Optional tumor biopsies for research purposes will be performed at baseline prior to study treatment and at the beginning of cycle 7 (+/- one cycle)
• Restaging scans (magnetic resonance imaging (MRI) with diffusion weighting) will be performed at baseline, at the end of cycles 1 and 6, and then every 6 cycles
• Health-related quality of life (HRQOL)/symptom questionnaires will be administered at baseline and at each Clinical Center visit

Conditions

Desmoid Tumors; Aggressive Fibromatosis

Keywords

Desmoid Tumor; Aggressive Fibromatosis; Gamma-secretase Inhibitor; Notch Pathway

Outcome Measures

Primary Outcomes (1)

• Number of Participants With a Complete Response (CR) + Partial Response (PR)

  Complete Response + Partial Response was determined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD) is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progressions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

  20 months

Secondary Outcomes (3)

• Number of Participants With Serious and Non-serious Adverse Events

  Date treatment consent signed to date off study, approximately 66 months and 27 days.

• Number of Participants With Somatic or Germline Mutations Identified in Adenomatous Polyposis Coli Gene (APC) or Catenin Beta-1 (CTNNB1) Genes

  Baseline

• Mean MD Anderson Symptom Inventory Scores After Treatment

  At baseline prior to drug administration and at least every 6 cycles of drug (18 weeks) up to 20 months of treatment.

Study Arms (1)

PF-03084014 in Desmoid Tumors/Aggressive Fibromatosis

EXPERIMENTAL

PF-03084014 will be administered orally at 150 mg twice a day in 21-day cycles

Drug: PF-03084014

Interventions

PF-03084014 DRUG

Treatment with the selective small-molecule \>=-secretase inhibitor PF- 3084014 caused significant tumor shrinkage in patients with unresectable desmoid tumors in an early-phase clinical trial.

PF-03084014 in Desmoid Tumors/Aggressive Fibromatosis

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically confirmed desmoid tumor confirmed by the Laboratory of Pathology, National Cancer Institute (NCI), that has progressed after receiving at least one line of standard treatment and that is not amenable to surgical resection or definitive radiation therapy.
• Willingness to provide blood samples and 10 unstained slides or a tumor block for genetic research studies.
• Any line of therapy with prior desmoid therapy, including radiotherapy, should have been completed at least 2 weeks before study entry and all toxicities must have resolved at least to eligibility levels.
• Age greater than or equal 18 years; because no dosing or adverse event data are currently available on the use of PF-03084014 in patients \<18 years of age, children are excluded from this study, but may be eligible for future pediatric trials.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal 2.
• Life expectancy \> 3 months.
• Patients must have normal organ and marrow function as defined below:
• absolute neutrophil count greater than or equal 1,500/mcL
• platelets greater than or equal 100,000/mcL
• total bilirubin less than or equal 1.5 times institutional upper limit of normal
• Aspartate aminotransferase (AST) Serum Glutamic Oxaloacetic Transaminase (SGOT)/Alanine aminotransferase (ALT) Serum glutamic-pyruvic transaminase (SGPT) less than or equal 5 times institutional upper limit of normal
• creatinine \< 1.5 times institutional upper limit of normal
• creatinine clearance greater than or equal 60 mL/min/1.73 m(2) for patients with creatinine levels \>1.5 mg/dL
• hemoglobin greater than or equal 9 g/dL
• Patients must be able to swallow whole tablets or capsules with no gastrointestinal (GI) condition affecting absorption; nasogastric or G-tube administration is not allowed.

You may not qualify if:

• Patients who are receiving any other investigational agents. Concurrent mediations that the patient is taking will be reviewed by the principal investigator (PI) to assess safety and eligibility.
• Prior treatment with Gamma-secretase inhibitors or anti-notch antibody therapy.
• Uncontrolled intercurrent illness including, but not limited to, serious infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Corrected QT interval (QTc) interval of \>470 msec at study entry; congenital long QT syndrome.
• Pregnant women are excluded from this study because PF-03084014 is a Gamma-secretase inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with PF-03084014, breastfeeding should be discontinued if the mother is treated with PF-03084014.
• Patients with gastrointestinal conditions that might predispose for drug intolerability or poor drug absorption (e.g., inability to take oral medication or a requirement for intravenous (IV) alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded. Subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow the tablet whole. Tablets must not be crushed or chewed; nasogastric or gastrostomy (G)-tube administration is not allowed.
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with PF-03084014.
• Recruitment Strategies
• We have had multiple discussions with the Desmoid Tumor Research Foundation, Inc., who have various outreach efforts including patient meetings and webcasts. Senior executives of the Foundation have indicated strong interest in this trial and willingness to inform their members. We also have a network of referring physicians nationally that refers patients with solid tumors to our clinical program. Given our interest and trials for sarcomas, we have formed connections with centers that treat patients with mesenchymal malignancies. We will be informing all of these of the availability of this trial once it is open.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• de Bree E, Keus R, Melissas J, Tsiftsis D, van Coevorden F. Desmoid tumors: need for an individualized approach. Expert Rev Anticancer Ther. 2009 Apr;9(4):525-35. doi: 10.1586/era.09.9.

  PMID: 19374605 BACKGROUND

• Lev D, Kotilingam D, Wei C, Ballo MT, Zagars GK, Pisters PW, Lazar AA, Patel SR, Benjamin RS, Pollock RE. Optimizing treatment of desmoid tumors. J Clin Oncol. 2007 May 1;25(13):1785-91. doi: 10.1200/JCO.2006.10.5015.

  PMID: 17470870 BACKGROUND

• Lewis JJ, Boland PJ, Leung DH, Woodruff JM, Brennan MF. The enigma of desmoid tumors. Ann Surg. 1999 Jun;229(6):866-72; discussion 872-3. doi: 10.1097/00000658-199906000-00014.

  PMID: 10363901 BACKGROUND

• Kummar S, O'Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E, Choyke PL, Meehan R, Vilimas R, Horneffer Y, Juwara L, Lih A, Choudhary A, Mitchell SA, Helman LJ, Doroshow JH, Chen AP. Clinical Activity of the gamma-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis). J Clin Oncol. 2017 May 10;35(14):1561-1569. doi: 10.1200/JCO.2016.71.1994. Epub 2017 Mar 28.

  PMID: 28350521 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Desmoid Tumors

Interventions

nirogacestat

Condition Hierarchy (Ancestors)

Fibroma; Neoplasms, Fibrous Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Results Point of Contact

• Title: Dr. Geraldine H O'Sullivan Coyne
• Organization: National Cancer Institute

osullivancoyngh@nci.nih.gov

240-781-3371

Study Officials

• Geraldine H O'Sullivan Coyne, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Investigator

Study Record Dates

• First Submitted: October 31, 2013
• First Posted: November 11, 2013
• Study Start: October 31, 2013
• Primary Completion: December 30, 2018
• Study Completion: December 1, 2023
• Last Updated: February 6, 2024
• Results First Posted: February 5, 2020

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Clinical data available during the study and indefinitely.
• Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI).

Locations

US (1)