PTC299 in Treating Patients With HIV-Related Kaposi Sarcoma

NCT00686842 | Terminated Phase 1 Results

• 4 other identifiers: AMC-059U01CA121947CDR0000596565PTC299-ONC-005-KS
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 8

Brief Summary

RATIONALE: PTC299 may stop the growth of Kaposi sarcoma by blocking blood flow to the tumor. PURPOSE: This phase I/II trial is studying the side effects and best dose of PTC299 and to see how well it works in treating patients with HIV-related Kaposi sarcoma.

Conditions

Kaposi's Sarcoma

Keywords

HIV infection; AIDS-related Kaposi sarcoma; recurrent Kaposi sarcoma; Treatment Experienced

Outcome Measures

Primary Outcomes (3)

• Safety and Toxicity of Anti-VEGF Small Molecule PTC299

  Patients who experienced an adverse event of grade 3 or greater

  All study visits

• Maximum Tolerated Dose

  After each group of 3 subjects completes cycle 1 of treatment

• Response to Treatment

  After each 28-day cycle of treatment and at discontinuation of therapy

Secondary Outcomes (6)

• Pharmacokinetics

  Days 1, 15, 28, 57

• Effects of Study Drug on Serum and Plasma VEGF, VEGFR, and Cytokine Profiles

  On the first day of every 28-day cycle of treatment, Day 15, and treatment discontinuation

• Effects of Study Drug on HIV and KSHV Viral Loads

  Screening, end of cycle 1, end of every third cycle thereafter, and treatment discontinuation

• Effects of Study Drug on T-lymphocyte Subsets (i.e., CD4 and CD8)

  Screening, day 29, every 3 cycles thereafter, and at treatment discontinuation

• Effects of Study Drug on VEGF, VEGFR-2 and -3, Phospho-Akt, p53, and HIF-1α Expression and Tumor Cell Proliferation, as Measured by Ki-67 Staining, in Tumor Biopsy Samples

  Screening and day 28

Study Arms (1)

VEGF Inhibitor PTC299

EXPERIMENTAL

Single arm study - all subjects received PTC299

Drug: VEGF inhibitor PTC299; Genetic: gene expression analysis; Genetic: polymerase chain reaction; Genetic: protein expression analysis; Other: immunohistochemistry staining method; Other: laboratory biomarker analysis; Other: pharmacological study; Procedure: biopsy

Interventions

VEGF inhibitor PTC299 DRUG

20 mg capsules to be taken by mouth BID. Three dose levels will be evaluated: 40 mg, 80mg, and 100mg BID. Subjects will receive PTC299 in consecutive 28-day cycles for a maximum of 12 cycles.

VEGF Inhibitor PTC299

gene expression analysis GENETIC

To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.

VEGF Inhibitor PTC299

polymerase chain reaction GENETIC

To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.

VEGF Inhibitor PTC299

protein expression analysis GENETIC

To describe the effects of PTC299 on viral gene expression and cellular gene transcription in KS tumor biopsies using real-time QPCR-based profiling.

VEGF Inhibitor PTC299

immunohistochemistry staining method OTHER

To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.

VEGF Inhibitor PTC299

laboratory biomarker analysis OTHER

To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.

VEGF Inhibitor PTC299

pharmacological study OTHER

To describe the pharmacokinetics of PTC299 in patients with HIV-associated KS. To describe the effects of PTC299 on circulating VEGF, VEGFR and cytokine levels in patients with HIV-associated KS.

VEGF Inhibitor PTC299

biopsy PROCEDURE

To describe the effects of PTC299 on KS tumor biopsies with respect to expression of VEGF, the VEGFR-2 and -3, phospho-Akt, p53, HIF-1α and proliferation, measured by Ki-67 staining.

VEGF Inhibitor PTC299

Eligibility Criteria

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

DISEASE CHARACTERISTICS: * Biopsy-proven Kaposi sarcoma (KS) involving the skin (with or without lymph node), oral cavity, gastrointestinal (GI) tract, and/or lung * Patients with GI and/or pulmonary involvement must be asymptomatic or minimally symptomatic and not require systemic cytotoxic chemotherapy * Has at least five bidimensionally measurable cutaneous lesions that have not been previously irradiated AND can be used as indicator lesions * Must have a sufficient number of non-indicator cutaneous lesions measuring ≥ 4 x 4 mm available to obtain a total of four 3-mm punch biopsies (two at baseline and two during the course of study treatment) * Serologic documentation of HIV infection, as evidenced by positive ELISA, western blot, or other federally approved licensed HIV test OR a detectable blood level of HIV RNA * Patients receiving antiretroviral therapy for HIV infection are eligible provided they have been on a stable regimen for ≥ 12 weeks prior to study entry AND there is no evidence of improvement in KS during those 12 weeks or there is evidence of progression of KS within the immediate 4 weeks prior to study entry * No symptomatic visceral KS requiring cytotoxic therapy PATIENT CHARACTERISTICS: * Karnofsky performance status 60-100% * Life expectancy ≥ 3 months * Absolute neutrophil count ≥ 1,000/mm³ * Platelet count ≥ 75,000/mm³ * Hemoglobin ≥ 8 g/dL * Creatinine ≤ 2.0 mg/dL * Total bilirubin normal (grade 0) * No specific limit of total serum bilirubin for patient receiveing indinavir or atazanavir therapy AND direct serum bilirubin ≤ 30% of total bilirubin * AST and ALT ≤ 2.5 times upper limit of normal (grade 1) * INR and aPTT normal * Proteinuria \< 2+ * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective barrier contraception during and for up to 3 months after completion of study treatment * Capable of complying with the study, in the opinion of the investigator * No acute, active opportunistic infection (other than oral thrush or genital herpes) within the past 14 days * No other concurrent neoplasia requiring cytotoxic therapy * No history of any of the following: * Myocardial infarction * Severe/unstable angina * Coronary/peripheral artery bypass graft * Symptomatic congestive heart failure * Cerebrovascular accident * Transient ischemic attack * Pulmonary embolism * Deep vein thrombosis * Other significant thromboembolic event * No known coagulopathy or bleeding diathesis * No history of CNS, pulmonary, GI, or urinary bleeding * No known history of drug-induced liver injury * Resting systolic blood pressure ≤ 160 mm Hg or diastolic blood pressure ≤ 100 mm Hg * No history of or ongoing clinically significant illness, medical condition, surgical history, physical finding, ECG finding, or laboratory abnormality that, in the opinion of the investigator, could affect the safety of the patient, alter the absorption of the study drug, or impair the assessment of study results PRIOR CONCURRENT THERAPY: * More than 4 weeks since prior and no other concurrent anti-neoplastic therapy for KS, including chemotherapy, radiotherapy, local therapy, or biological therapy * More than 60 days since prior local therapy for any KS-indicator lesion unless the lesion has clearly progressed since treatment * Any prior local therapy for indicator lesions (regardless of the elapsed time) should not be allowed unless there is evidence of clear-cut progression of that lesion * More than 28 days since prior and no other concurrent investigational drugs or therapy (other than antiretroviral therapy or agents available on a treatment IND) * More than 30 days since prior major surgery and recovered * More than 14 days since prior treatment for an acute infection (other than oral thrush or genital herpes) or other serious medical illness * No concurrent surgical procedures * No concurrent systemic corticosteroid therapy, other than replacement doses * No concurrent anticoagulant therapy, including warfarin, heparin (including low molecular weight heparin), or antiplatelet drugs (e.g., clopidogrel bisulfate) * Concurrent aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) allowed provided the dose does not exceed the maximum recommended dose

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• AIDS Malignancy Consortium: lead
• National Cancer Institute (NCI): collaborator
• PTC Therapeutics: collaborator
• The Emmes Company, LLC: collaborator

Study Sites (8)

Rebecca and John Moores UCSD Cancer Center

La Jolla, California, 92093-0658, United States

Location

USC/Norris Comprehensive Cancer Center and Hospital

Los Angeles, California, 90033-1048, United States

Location

UCLA Clinical AIDS Research and Education (CARE) Center

Los Angeles, California, 90095-1793, United States

Location

Cancer Research Center of Hawaii

Honolulu, Hawaii, 96813, United States

Location

Beth Israel Deaconess Medical Center

Boston, Massachusetts, 02215, United States

Location

Memorial Sloan-Kettering Cancer Center

New York, New York, 10065, United States

Location

Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210-1240, United States

Location

Floyd and Delores Jones Cancer Institute at Virginia Mason Medical Center

Seattle, Washington, 98111, United States

Location

Related Publications (1)

• Bender Ignacio RA, Lee JY, Rudek MA, Dittmer DP, Ambinder RF, Krown SE; AIDS Malignancy Consortium (AMC)-059 Study Team. Brief Report: A Phase 1b/Pharmacokinetic Trial of PTC299, a Novel PostTranscriptional VEGF Inhibitor, for AIDS-Related Kaposi's Sarcoma: AIDS Malignancy Consortium Trial 059. J Acquir Immune Defic Syndr. 2016 May 1;72(1):52-7. doi: 10.1097/QAI.0000000000000918.

  PMID: 26689971 BACKGROUND

MeSH Terms

Conditions

Sarcoma, Kaposi; HIV Infections; AIDS-related Kaposi sarcoma

Interventions

emvododstat; Gene Expression Profiling; Polymerase Chain Reaction; Immunohistochemistry; Biopsy

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Vascular Tissue; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Genetic Techniques; Investigative Techniques; Nucleic Acid Amplification Techniques; Histocytochemistry; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Histological Techniques; Immunologic Techniques; Cytodiagnosis; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative

Results Point of Contact

• Title: Susan Krown, MD, Protocol Chair
• Organization: AMC

amcpm@emmes.com

301-251-1161

Study Officials

• Susan E. Krown, MD

  Memorial Sloan Kettering Cancer Center

  STUDY CHAIR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 29, 2008
• First Posted: May 30, 2008
• Study Start: September 1, 2008
• Primary Completion: November 1, 2010
• Study Completion: December 1, 2010
• Last Updated: June 6, 2018
• Results First Posted: March 5, 2012

Record last verified: 2018-05

Locations

US (8)