PCI-24781 in Combination With Doxorubicin to Treat Sarcoma

NCT01027910 | Completed Phase 1 Results DMC

• 1 other identifier: 09-352
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

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.

Conditions

Sarcoma

Keywords

PCI-24781; doxorubicin

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerated Dose

  up to 30 days after starting study drugs

Secondary Outcomes (3)

• Dose Limiting Toxicities

  1 year

• Number of Partial Responses (PR)

  1 year

• Rate of Progression-free Survival at 6 Months in Participants Who Received PCI-24781/Doxorubicin Combination Administration.

  2 years

Study Arms (2)

PCI-24781 without mandated GCSF

EXPERIMENTAL

PCI-24781 in combination with doxorubicin without mandated GCSF

Drug: PCI-24781; Drug: Doxorubicin; Drug: GCSF

PCI-24781 with mandated GCSF

EXPERIMENTAL

PCI-24781 in combination with doxorubicin with mandated GCSF

Drug: PCI-24781; Drug: Doxorubicin; Drug: GCSF

Interventions

PCI-24781 DRUG

Capsules taken orally for 5 consecutive days starting on Day 1 of each 3 week cycle

Also known as: PCI24781

PCI-24781 with mandated GCSF; PCI-24781 without mandated GCSF

Doxorubicin DRUG

Administered intravenously on Day 4 of each 3 week cycle

Also known as: Adriamycin

PCI-24781 with mandated GCSF; PCI-24781 without mandated GCSF

GCSF DRUG

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

Also known as: Neupogen

PCI-24781 with mandated GCSF; PCI-24781 without mandated GCSF

Eligibility Criteria

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

You may qualify if:

• 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.
• years of age or older

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02115, United States

Location

Related Publications (7)

• Lopez G, Liu J, Ren W, Wei W, Wang S, Lahat G, Zhu QS, Bornmann WG, McConkey DJ, Pollock RE, Lev DC. Combining PCI-24781, a novel histone deacetylase inhibitor, with chemotherapy for the treatment of soft tissue sarcoma. Clin Cancer Res. 2009 May 15;15(10):3472-83. doi: 10.1158/1078-0432.CCR-08-2714. Epub 2009 May 5.

  PMID: 19417021 BACKGROUND

• Buggy JJ, Cao ZA, Bass KE, Verner E, Balasubramanian S, Liu L, Schultz BE, Young PR, Dalrymple SA. CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo. Mol Cancer Ther. 2006 May;5(5):1309-17. doi: 10.1158/1535-7163.MCT-05-0442.

  PMID: 16731764 BACKGROUND

• Adimoolam S, Sirisawad M, Chen J, Thiemann P, Ford JM, Buggy JJ. HDAC inhibitor PCI-24781 decreases RAD51 expression and inhibits homologous recombination. Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19482-7. doi: 10.1073/pnas.0707828104. Epub 2007 Nov 27.

  PMID: 18042714 BACKGROUND

• Yang C, Choy E, Hornicek FJ, Wood KB, Schwab JH, Liu X, Mankin H, Duan Z. Histone deacetylase inhibitor PCI-24781 enhances chemotherapy-induced apoptosis in multidrug-resistant sarcoma cell lines. Anticancer Res. 2011 Apr;31(4):1115-23.

  PMID: 21508354 BACKGROUND

• Yang C, Choy E, Hornicek FJ, Wood KB, Schwab JH, Liu X, Mankin H, Duan Z. Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells. Cancer Chemother Pharmacol. 2011 Feb;67(2):439-46. doi: 10.1007/s00280-010-1344-7. Epub 2010 May 12.

  PMID: 20461381 BACKGROUND

• Lopez G, Torres K, Liu J, Hernandez B, Young E, Belousov R, Bolshakov S, Lazar AJ, Slopis JM, McCutcheon IE, McConkey D, Lev D. Autophagic survival in resistance to histone deacetylase inhibitors: novel strategies to treat malignant peripheral nerve sheath tumors. Cancer Res. 2011 Jan 1;71(1):185-96. doi: 10.1158/0008-5472.CAN-10-2799. Epub 2010 Nov 16.

  PMID: 21084276 BACKGROUND

• Choy E, Flamand Y, Balasubramanian S, Butrynski JE, Harmon DC, George S, Cote GM, Wagner AJ, Morgan JA, Sirisawad M, Mani C, Hornicek FJ, Duan Z, Demetri GD. Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma. Cancer. 2015 Apr 15;121(8):1223-30. doi: 10.1002/cncr.29175. Epub 2014 Dec 23.

  PMID: 25536954 BACKGROUND

MeSH Terms

Conditions

Sarcoma

Interventions

abexinostat; Doxorubicin; Filgrastim

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Granulocyte Colony-Stimulating Factor; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Results Point of Contact

• Title: Dr. Edwin Choy
• Organization: Massachusetts General Hospital

echoy@mgh.harvard.edu

617-724-4000

Study Officials

• Edwin Choy, MD, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: December 8, 2009
• First Posted: December 9, 2009
• Study Start: February 1, 2009
• Primary Completion: March 1, 2015
• Study Completion: March 1, 2015
• Last Updated: July 24, 2025
• Results First Posted: February 14, 2017

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)