A Study of AT1001 in Patients With Fabry Disease

Brief Title

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

Official Title

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

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
    

Detailed Description

      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

        -  Exploratory: 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 (computed tomography (CT) scan of the known site of disease) will be
           performed at baseline and then every 6 cycles (+/- one cycle)

        -  Optional magnetic resonance imaging (MRI) scans may be performed prior to start of study
           treatment, end of cycle 1, and every 6 cycles (at the same times as the CT scans)

        -  Health-related quality of life (HRQOL)/symptom questionnaires will be administered at
           baseline and at restaging
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

 Number of Participants With Serious and Non-serious Adverse Events

Condition

Desmoid Tumors

Intervention

PF-03084014

Study Arms / Comparison Groups

 PF-03084014 in Desmoid Tumors/Aggressive Fibromatosis
Description:  PF-03084014 will be administered orally at 150 mg twice a day in 21-day cycles

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

17

Start Date

October 31, 2013

Completion Date

October 12, 2020

Primary Completion Date

December 30, 2018

Eligibility Criteria

        -  INCLUSION CRITERIA:

        2.1.1.1 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.

        2.1.1.2 Willingness to provide blood samples and 10 unstained slides or a tumor block for
        genetic research studies.

        2.1.1.3 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.

        2.1.1.4 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.

        2.1.1.5 Eastern Cooperative Oncology Group (ECOG) performance status less than or equal 2.

        2.1.1.6 Life expectancy > 3 months.

        2.1.1.7 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

        OR

          -  -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

        2.1.1.8 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.

        2.1.1.9 The effects of PF-03084014 on the developing human fetus are unknown. For this
        reason and because >=-secretase inhibitors are known to be teratogenic, women of
        childbearing potential and men must agree to use adequate contraception (hormonal or
        barrier method of birth control; abstinence) for the duration of study participation and
        for at least 6 months after dosing with study drugs ceases. Should a woman become pregnant
        or suspect she is pregnant while she or her partner is participating in this study, she
        should inform her treating physician immediately. Men treated or enrolled on this protocol
        must also agree to use adequate contraception for the duration of study participation, and
        6 months after completion of study drug administration.

        2.1.1.10 Ability to understand and the willingness to sign a written informed consent
        document.

        2.1.1.11 Evidence of measurable disease by computed tomography (CT) scan. Measurable
        lesions are defined as those that can be accurately measured in at least one dimension
        (longest diameter to be recorded) as greater than or equal 20 mm by chest x-ray, as greater
        than or equal 10 mm with CT scan, or greater than or equal 10 mm with calipers by clinical
        exam.

        EXCLUSION CRITERIA:

        2.1.2.1 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.

        2.1.2.2 Prior treatment with Gamma-secretase inhibitors or anti-notch antibody therapy.

        2.1.2.3 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.

        2.1.2.4 Corrected QT interval (QTc) interval of >470 msec at study entry; congenital long
        QT syndrome.

        2.1.2.5 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.

        2.1.2.6 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.

        2.1.2.7 Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
        therapy are ineligible because of the potential for pharmacokinetic interactions with
        PF-03084014.

        2.1.3 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.
      

Gender

All

Ages

18 Years - 120 Years

Accepts Healthy Volunteers

No

Contacts

Geraldine H O'Sullivan Coyne, M.D., , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT01981551

Organization ID

140007

Secondary IDs

14-C-0007

Responsible Party

Principal Investigator

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Geraldine H O'Sullivan Coyne, M.D., Principal Investigator, National Cancer Institute (NCI)


Verification Date

January 2020