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PCI-24781 in Combination With Doxorubicin to Treat Sarcoma

Sponsor
Massachusetts General Hospital (Other)
Overall Status
Completed
CT.gov ID
NCT01027910
Collaborator
Dana-Farber Cancer Institute (Other), Brigham and Women's Hospital (Other), Pharmacyclics LLC. (Industry)
20
Enrollment
2
Locations
2
Arms
72.9
Duration (Months)
10
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this research study is to determine the safety and maximum tolerated dose of PCI-24781 that can be given safely with doxorubicin (phase I) and the safety and efficacy of PCI-24781 when used in combination with doxorubicin (phase II) in patients with advanced sarcomas. The study drug, PCI-24781, is believed to regulate genes involved in tumor cell growth. The other study drug, doxorubicin, is considered a standard chemotherapeutic treatment for advanced sarcoma patients. We hypothesize that combining PCI-24781 with doxorubicin can overcome chemoresistance to doxorubicin.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

  • In the phase I portion of the study, since we are looking for the highest dose of PCI-24781 that can be administered safely without severe or unmanageable side effects in participants that have advanced sarcoma, not everyone who participates in this research study will receive the same dose of PCI-24871.

  • Each treatment cycle is 3 weeks (21 days). Participants will take capsules of PCI-24871 for five consecutive days starting on Day 1 of each 3 week cycle. On Day 4 of each cycle, participants will come to the clinic to receive doxorubicin intravenously.

  • At specific time intervals, participants will return to the clinic for the following tests and procedures: physical examination, vital signs, blood tests, urine test, EKG, assessment of the tumor by CT scan, and an ECHO or MUGA.

  • Participants may remain on the study for a maximum of 6 cycles (about 4-5 months). After the last cycle, as long as the participant is showing benefit, they may elect to continue taking PCI-24781 alone, in which case they will continue in this research study until there is evidence of their tumor growing.

Study Design

Study Type:
Interventional
Actual Enrollment :
20 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Phase I/II Study of PCI-24781 in Combination With Doxorubicin for Treatment of Advanced Sarcomas Following Failure or Prior Anthracycline Therapy
Study Start Date :
Feb 1, 2009
Actual Primary Completion Date :
Mar 1, 2015
Actual Study Completion Date :
Mar 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: PCI-24781 without mandated GCSF

PCI-24781 in combination with doxorubicin without mandated GCSF

Drug: PCI-24781
Capsules taken orally for 5 consecutive days starting on Day 1 of each 3 week cycle
Other Names:
  • PCI24781

    • Drug: Doxorubicin
    Administered intravenously on Day 4 of each 3 week cycle
    Other Names:
  • Adriamycin

    • Drug: GCSF
    Administered on Day 5 of each 3 weeks cycle in Arm 1 if determined to be clinically indicated, and in all patients enrolled into Arm 2
    Other Names:
  • Neupogen

    		•
    Experimental: PCI-24781 with mandated GCSF

    PCI-24781 in combination with doxorubicin with mandated GCSF

    Drug: PCI-24781
    Capsules taken orally for 5 consecutive days starting on Day 1 of each 3 week cycle
    Other Names:
  • PCI24781

    • Drug: Doxorubicin
    Administered intravenously on Day 4 of each 3 week cycle
    Other Names:
  • Adriamycin

    • Drug: GCSF
    Administered on Day 5 of each 3 weeks cycle in Arm 1 if determined to be clinically indicated, and in all patients enrolled into Arm 2
    Other Names:
  • Neupogen

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose [up to 30 days after starting study drugs]

    Secondary Outcome Measures

    1. Dose Limiting Toxicities [1 year]

      number of patients who experienced dose limiting toxicities

    2. Number of Partial Responses (PR) [1 year]

      number of patients who demonstrated partial response to therapy as determined by RECIST v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

    3. Rate of Progression-free Survival at 6 Months in Participants Who Received PCI-24781/Doxorubicin Combination Administration. [2 years]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Participants must have histologically confirmed metastatic or unresectable sarcoma

    • All participants must have received no more than a lifetime cumulative maximum dose of 300 mg/m2 or less of prior doxorubicin and no other anthracycline therapy.

    • Participants must have measurable disease, defined as at least one unirradiated lesion that can be accurately measured in at least one dimension as 20mm or greater with conventional techniques or as 10mm or greater with spiral CT scan.

    • ECOG performance status of 2 or less

    • Ability to swallow oral capsules without difficulty

    • Participants must have normal organ and marrow function as outlined in the protocol.

    • Women of childbearing potential must have a negative serum/urine pregnancy test within 7 days prior to receiving the first dose of PCI-24781.

    • An ECHO or MUGA demonstrating EF > 50% is required within 4 weeks prior to study drug administration.

    • 18 years of age or older

    Exclusion Criteria:

    • Participants who have had immunotherapy, chemotherapy, experimental therapy or radiotherapy within 4 weeks before first day of study drug dosing or those who have not recovered to grade 1 or baseline from adverse events due to agents administered more than 4 weeks earlier.

    • Participants who have previously received > 300 mg/m2 cumulative lifetime dose of doxorubicin, or who have received any other anthracycline chemotherapy.

    • Major surgery within 4 weeks before first day of study drug dosing

    • Participants with known central nervous system/brain metastases

    • Participants receiving chronic corticosteroids > 20 mg prednisone equivalent per day for > 7 consecutive days (Topical, inhaled or nasal corticosteroids are permitted).

    • Participants with any documented malabsorption syndromes or other conditions that may impair the absorption of PCI-24781 capsules.

    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

    • Participants requiring concurrent therapeutic anticoagulation or have received therapeutic anticoagulation within 2 weeks of the first day of dosing.

    • Risk factors for Torsades de Pointes, or use, within 4 weeks of starting study drug administration, of medications known to prolong QTc interval or that may be associated with Torsades de Pointes.

    • QTc prolongation or other significant ECG abnormalities defined as 2nd degree AV block type II, 3rd degree AV block, or bradycardia.

    • History of myocardial infarction, acute coronary syndromes, coronary angioplasty and/or coronary artery stenting within the past 6 months.

    • For patients with history of major coronary artery disease in the judgement of the responsible physician, a cardiac stress test that demonstrates clinically significant abnormalities when performed within 28 days of first dose of study drug

    • Pregnant or breastfeeding women

    • Women of childbearing potential, or sexually active men unwilling to use adequate contraceptive protection during the course of the study

    • HIV-positive individuals

    • Other medical or psychiatric illness or organ dysfunction that, in the opinion of the investigator, would either compromise the patient's safety or interfere with the evaluation of the safety of PCI-24781

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Massachusetts General Hospital Boston Massachusetts United States 02114
    2 Dana-Farber Cancer Institute Boston Massachusetts United States 02115

    Sponsors and Collaborators

    • Massachusetts General Hospital
    • Dana-Farber Cancer Institute
    • Brigham and Women's Hospital
    • Pharmacyclics LLC.

    Investigators

    • Principal Investigator: Edwin Choy, MD, PhD, Massachusetts General Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    Responsible Party:
    Edwin Choy, MD, Principle Investigator, Massachusetts General Hospital
    ClinicalTrials.gov Identifier:
    NCT01027910
    Other Study ID Numbers:
    • 09-352
    First Posted:
    Dec 9, 2009
    Last Update Posted:
    Feb 14, 2017
    Last Verified:
    Dec 1, 2016
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Keywords provided by Edwin Choy, MD, Principle Investigator, Massachusetts General Hospital
    PCI-24781
    doxorubicin
    Additional relevant MeSH terms:
    Sarcoma
    Doxorubicin
    Abexinostat

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title PCI-24781 + Doxorubicin Without Mandatory GCSF PCI-24781 + Doxorubicin With Mandatory GCSF
    Arm/Group Description PCI-24781 + Doxorubicin without mandatory GCSF PCI-24781: Capsules taken orally for 5 consecutive days starting on Day 1 of each 3 week cycle Doxorubicin: Administered intravenously on Day 4 of each 3 week cycle PCI-24781 + Doxorubicin with mandatory GCSF PCI-24781: Capsules taken orally for 5 consecutive days starting on Day 1 of each 3 week cycle Doxorubicin: Administered intravenously on Day 4 of each 3 week cycle
    Period Title: Overall Study
    STARTED 6 14
    COMPLETED 6 14
    NOT COMPLETED 0 0

    Baseline Characteristics

    Arm/Group Title PCI-24781 + Doxorubicin Without Mandatory GCSF PCI-24781 + Doxorubicin With Mandatory GCSF Total
    Arm/Group Description Study participants were enrolled into two arms. Arm A administered abexinostat and doxorubicin with optional GCSF support. Arm B administered abexinostat and doxorubicin with required GCSF support to all participants. The study uses the standard 3 + 3 phase I dose escalation design. Three cohorts of 3-6 participants were enrolled in each arm and separate inter-cohort dose escalations were performed in up to three cohorts of 3-6 participants enrolled sequentially until the maximum tolerated dose (MTD) of the combination abexinostat with doxorubicin, without (Arm A) mandatory G-CSF support was established. Study participants were enrolled into two arms. Arm A administered abexinostat and doxorubicin with optional GCSF support. Arm B administered abexinostat and doxorubicin with required GCSF support to all participants. The study uses the standard 3 + 3 phase I dose escalation design. Three cohorts of 3-6 participants were enrolled in each arm and separate inter-cohort dose escalations were performed in up to three cohorts of 3-6 participants enrolled sequentially until the maximum tolerated dose (MTD) of the combination abexinostat with doxorubicin, with (Arm B) mandatory G-CSF support was established. Total of all reporting groups
    Overall Participants 6 14 20
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    52
    (14)
    56
    (14)
    54
    (14)
    Gender (Count of Participants)
    Female
    1
    16.7%
    7
    50%
    8
    40%
    Male
    5
    83.3%
    7
    50%
    12
    60%

    Outcome Measures

    1. Primary Outcome
    Title Maximum Tolerated Dose
    Description
    Time Frame up to 30 days after starting study drugs

    Outcome Measure Data

    Analysis Population Description
    The two groups differ in that GCSF was offered if clinically indicated in arm 1 while it was administered to all participants in arm 2.
    Arm/Group Title PCI-24781 + Doxorubicin Without Mandatory GCSF PCI-24781 With Mandatory GCSF
    Arm/Group Description
    Measure Participants 6 14
    Number [mg/m2]
    15
    45
    2. Secondary Outcome
    Title Dose Limiting Toxicities
    Description number of patients who experienced dose limiting toxicities
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Optional GCSF Mandatory GCSF
    Arm/Group Description
    Measure Participants 6 14
    Number [participants]
    2
    33.3%
    2
    14.3%
    3. Secondary Outcome
    Title Number of Partial Responses (PR)
    Description number of patients who demonstrated partial response to therapy as determined by RECIST v1.0 for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
    Time Frame 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Optional GCSF Mandatory GCSF
    Arm/Group Description
    Measure Participants 6 14
    Number [participants]
    0
    0%
    3
    21.4%
    4. Secondary Outcome
    Title Rate of Progression-free Survival at 6 Months in Participants Who Received PCI-24781/Doxorubicin Combination Administration.
    Description
    Time Frame 2 years

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Optional GCSF Mandatory GCSF
    Arm/Group Description
    Measure Participants 6 14
    Number [participants]
    1
    16.7%
    6
    42.9%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title PCI-24781+Dox Without Mandated GCSF PCI-24781+Dox With Mandated GCSF
    Arm/Group Description Patients in this arm were not mandated treatment with GCSF Patients in this are were mandated treatment with GCSF
    All Cause Mortality
    PCI-24781+Dox Without Mandated GCSF PCI-24781+Dox With Mandated GCSF
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    PCI-24781+Dox Without Mandated GCSF PCI-24781+Dox With Mandated GCSF
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 2/6 (33.3%) 2/14 (14.3%)
    Blood and lymphatic system disorders
    grade 3 or 4 neutropenia 0/6 (0%) 0 2/14 (14.3%) 2
    thrombocytopenia 1/6 (16.7%) 1 0/14 (0%) 0
    Infections and infestations
    infection 1/6 (16.7%) 1 0/14 (0%) 0
    Other (Not Including Serious) Adverse Events
    PCI-24781+Dox Without Mandated GCSF PCI-24781+Dox With Mandated GCSF
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/6 (16.7%) 0/14 (0%)
    Gastrointestinal disorders
    diarrhea 1/6 (16.7%) 1 0/14 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Dr. Edwin Choy
    Organization Massachusetts General Hospital
    Phone 617-724-4000
    Email echoy@mgh.harvard.edu
    Responsible Party:
    Edwin Choy, MD, Principle Investigator, Massachusetts General Hospital
    ClinicalTrials.gov Identifier:
    NCT01027910
    Other Study ID Numbers:
    • 09-352
    First Posted:
    Dec 9, 2009
    Last Update Posted:
    Feb 14, 2017
    Last Verified:
    Dec 1, 2016