Clinical trial NCT00686842: PTC299 in Treating Patients With HIV-Related Kaposi Sarcoma
Official title: A Phase I/II Trial of PTC299 in Patients With HIV-Related Kaposi's Sarcoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Kaposi's Sarcoma
Keywords: HIV infection
AIDS-related Kaposi sarcoma
recurrent Kaposi sarcoma
Treatment Experienced
Lead sponsor: AIDS Malignancy Consortium
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: PTC Therapeutics
name: The Emmes Company, LLC
First posted: 2008-05-30
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Detailed description: OBJECTIVES:

Primary

* To define the safety and toxicity of anti-VEGF small molecule PTC299 in patients with HIV-related Kaposi sarcoma.
* To establish the maximum tolerated dose of this drug in these patients.
* To estimate the response rate in patients treated with this drug.

Secondary

* To describe the pharmacokinetics of this drug in these patients.
* To describe the effects of this drug on serum and plasma VEGF, VEGFR, and cytokine profiles in these patients.
* To describe the effects of this drug on HIV and KSHV viral loads in these patients.
* To describe the effects of this drug on T-lymphocyte subsets (i.e., CD4 and CD8) in these patients.
* To describe the effects of this 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 obtained from these patients.
* To describe the effects of this drug on viral gene expression and cellular gene transcription, as measured by real-time quantitative PCR-based profiling, in tumor biopsy samples obtained from these patients.

OUTLINE: This is a multicenter, phase I dose-escalation study of anti-VEGF small molecule PTC299 followed by a phase II study.

Patients receive oral anti-VEGF small molecule PTC299 twice daily on days 1-28. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients who do not demonstrate an objective response of their Kaposi sarcoma (KS) lesions after 6 courses of treatment are removed from the study.

Patients undergo blood sample collection and punch biopsies periodically during study for correlative laboratory studies. Biopsy samples are assessed for VEGF, VEGFR-2, VEGFR-3, phospho-Akt, KSHV LANA, orf59, p53, and HIF-1α expression by IHC; tumor cell proliferation by Ki-67 staining; and viral gene expression at the messenger RNA level and KSHV transcription by real-time quantitative PCR-based profiling. Blood samples are assessed for pharmacokinetics and levels of secreted cytokines or other potential serum markers characteristic for KS.

After completion of study treatment, patients are followed at 30 days.

Eligibility criteria: 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

Primary outcomes:
measure: Safety and Toxicity of Anti-VEGF Small Molecule PTC299
timeFrame: All study visits
measure: Maximum Tolerated Dose
timeFrame: After each group of 3 subjects completes cycle 1 of treatment
measure: Response to Treatment
timeFrame: After each 28-day cycle of treatment and at discontinuation of therapy
Secondary outcomes:
measure: Pharmacokinetics
timeFrame: Days 1, 15, 28, 57
measure: Effects of Study Drug on Serum and Plasma VEGF, VEGFR, and Cytokine Profiles
timeFrame: On the first day of every 28-day cycle of treatment, Day 15, and treatment discontinuation
measure: Effects of Study Drug on HIV and KSHV Viral Loads
timeFrame: Screening, end of cycle 1, end of every third cycle thereafter, and treatment discontinuation
measure: Effects of Study Drug on T-lymphocyte Subsets (i.e., CD4 and CD8)
timeFrame: Screening, day 29, every 3 cycles thereafter, and at treatment discontinuation
measure: 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
timeFrame: Screening and day 28
measure: Effects of Study Drug on Viral Gene Expression and Cellular Gene Transcription, as Measured by Real-time Quantitative PCR-based Profiling, in Tumor Biopsy Samples
timeFrame: Screening and day 28
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Rebecca and John Moores UCSD Cancer Center
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Los Angeles
country: United States
facility: UCLA Clinical AIDS Research and Education (CARE) Center
state: California
city: Honolulu
country: United States
facility: Cancer Research Center of Hawaii
state: Hawaii
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
state: Ohio
city: Seattle
country: United States
facility: Floyd and Delores Jones Cancer Institute at Virginia Mason Medical Center
state: Washington
Study officials:
affiliation: Memorial Sloan Kettering Cancer Center
name: Susan E. Krown, MD
role: STUDY_CHAIR
References:
citation: 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.