Gamma Secretase Inhibitor PF-03084014 in Treating Patients With AIDS-Associated Kaposi Sarcoma

NCT02137564 | Withdrawn Phase 2

• 3 other identifiers: AMC-089NCI-2014-00638U01CA121947
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This phase II trial studies the effects, good and bad, of gamma secretase inhibitor PF-03084014 and to see how well it works in treating patients with acquired immune deficiency virus (AIDS)-associated Kaposi sarcoma. Gamma secretase inhibitor PF-03084014 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and may shrink the tumor.

Conditions

AIDS-related Kaposi Sarcoma; HIV Infection; Recurrent Kaposi Sarcoma

Outcome Measures

Primary Outcomes (2)

• Overall clinical response (PR and CR)

  The results of tumor evaluations will be tabulated. Binomial probabilities and their 95% confidence intervals will be used to estimate the response rates (i.e., overall response rate, partial response rate, complete response rate).

  Up to 28 days after completion of study treatment

• Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 (NCI CTCAE v4.0)

  The results of the safety evaluation will be tabulated. The frequency of adverse events (AEs) and their severity will be tabulated to evaluated tolerance.

  Up to 28 days after completion of study treatment

Secondary Outcomes (5)

• Levels of HIV virus load in plasma

  Up to 168 days

• CD4+ cell number

  Up to day 168 days

• Change in gene expression in tumor samples measured via reverse transcriptase polymerase chain reaction (RT-PCR)

  Baseline to up to day 8

• Activation of Notch target genes in tumor samples, measured via RT-PCR

  Baseline to up to day 8

• Trough gamma secretase inhibitor PF-03084014 drug levels

  Up to day 22

Study Arms (1)

Treatment (gamma secretase inhibitor PF-03084014)

EXPERIMENTAL

Patients receive gamma secretase inhibitor PF-03084014 PO BID on days 1-21. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients with PR, CR, or SD at the end of 4 courses may receive an additional 4 courses of gamma secretase inhibitor PF-03084014 in the absence of disease progression or unacceptable toxicity.

Drug: gamma secretase inhibitor PF-03084014; Other: pharmacological study; Other: laboratory biomarker analysis

Interventions

gamma secretase inhibitor PF-03084014 DRUG

Given PO

Also known as: PF-03084014

Treatment (gamma secretase inhibitor PF-03084014)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (gamma secretase inhibitor PF-03084014)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (gamma secretase inhibitor PF-03084014)

Eligibility Criteria

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

You may qualify if:

• Biopsy-proven KS involving skin, with or without visceral involvement, either newly diagnosed or refractory to or intolerant of one or more prior therapies
• Participants must have cutaneous lesion(s) amenable to four total biopsies (either four lesions \> 4 mm or one large lesion measuring 20 mm that can undergo serial biopsy) and at least five additional lesions measurable for assessment with no improvement over the past month
• There should be no evidence for improvement in KS in the 3 months prior to study entry, unless there is also evidence for progression of KS in the 4 weeks immediately prior to study entry
• Serologic documentation of HIV infection by any of the Food and Drug Administration (FDA)-approved tests
• Karnofsky performance status \>= 60%
• All participants must be on antiretroviral therapy for HIV infection with CD4 count \> 50/mm\^3 and viral load \< 2,000 copies/mL; participants must be on a stable regimen for at least 12 weeks prior to study entry; participants may receive any FDA approved antiretroviral therapy except for zidovudine or boosted protease inhibitors
• If antiretroviral regimen contains zidovudine or strong cytochrome P450, family 3, subfamily A, polypeptide 4 (Cyp3A4) inhibitors (e.g. ritonavir or cobicistat-boosted protease inhibitors) and viral load is suppressed (as measured by HIV viral load =\< 200/mL), then antiretroviral therapy must be adjusted to a less toxic therapy not containing these antivirals and enrollment may proceed without waiting 12 weeks
• If on antiviral therapy with zidovudine or boosted protease inhibitors, and viral load is not suppressed (as measured by HIV viral load \>= 200/mL), then antiretroviral therapy must be adjusted to a less toxic regimen allowing for optimal viral suppression and must demonstrate stability for at least 12 weeks prior to study entry
• Allowable antiretrovirals include nucleoside or nucleotide inhibitors other than zidovudine, non-nucleoside inhibitors, non-boosted protease inhibitors, integrase inhibitors raltegravir or dolutegravir, or entry inhibitors maraviroc or enfuvirtide
• Hemoglobin \>= 8 g/dL
• Absolute neutrophil count (ANC) \>= 1,000 cells/mm\^3
• Platelet count \>= 100,000/mm\^3
• Calculated (method of Cockcroft-Gault) creatinine clearance (CrCl) \>= 60 mL/min (creatinine clearance may also be obtained by the 24-hour collection method at the investigator's discretion)
• Total bilirubin should be =\< 1.5 x upper limit of normal (ULN); if, however, the elevated bilirubin is felt to be secondary to atazanavir therapy, participants will be allowed to enroll on protocol if the total bilirubin is =\< 3.5 mg/dL provided that the direct bilirubin is normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 3 x ULN

You may not qualify if:

• Concurrent, acute, active opportunistic infection other than oral thrush or genital herpes within 14 days of enrollment
• Acute treatment for an infection (other than oral thrush or genital herpes) or other serious medical illness within 14 days of study entry
• Participants for whom front-line cytotoxic therapy is indicated (i.e., symptomatic visceral or pulmonary KS or symptomatic KS impairing functional status); all participants must have a chest X-ray to rule out pulmonary KS within 28 days of study enrollment
• Concurrent neoplasia requiring cytotoxic therapy
• Anti-neoplastic treatment for KS (including chemotherapy, radiation therapy, local therapy including topical fluorouracil \[5-FU\], biological therapy, or investigational therapy) within four weeks of study entry
• Any steroid treatment except for that required for replacement therapy in adrenal insufficiency or inhaled steroids for the treatment of asthma
• Patient is =\< 2 years free of another primary malignancy; exceptions include the following:
• Cervical carcinoma in situ
• Anal carcinoma in situ
• Previous local therapy of any KS-indicator lesion unless the lesion has clearly progressed since treatment; any prior local treatment to indicator lesions regardless of the elapsed time is not allowed unless there is evidence of clear-cut progression of said lesion
• Use of any investigational drug or treatment within 4 weeks prior to enrollment
• Physical or psychiatric conditions that in the estimation of the investigator place the patient at high risk of toxicity or non-compliance
• Female participants who are breast-feeding
• Participants requiring blood transfusions to maintain hemoglobin (Hgb) eligibility
• Participants currently receiving zidovudine, or strong CYP3A4 inhibitors (e.g. cobicistat (currently only in Stribild® or ritonavir boosted antiretroviral regimens), ketoconazole, itraconazole, erythromycin, clarithromycin, dexamethasone, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, St John's Wort, tacrolimus, cyclosporine, oral contraceptives, warfarin, docetaxel, sirolimus, or other strong inhibitors or inducers of CYP3A4 or substrates of CYP3A4 that have a narrow therapeutic margin

Sponsors & Collaborators

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

MeSH Terms

Conditions

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

Interventions

nirogacestat

Condition Hierarchy (Ancestors)

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

Study Officials

• Lee Ratner

  AIDS Associated Malignancies Clinical Trials Consortium

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 9, 2014
• First Posted: May 14, 2014
• Study Start: July 1, 2015
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: July 23, 2015

Record last verified: 2015-07