AzTrials
AzTrials

AIDS-related Kaposi SarcomaPhase 2NCT02137564

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

A Phase 2 study testing gamma secretase inhibitor PF-03084014, pharmacological study and laboratory biomarker analysis in people with AIDS-related Kaposi Sarcoma and HIV Infection, run by AIDS Malignancy Consortium.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
gamma secretase inhibitor PF-03084014, pharmacological study and laboratory biomarker analysis
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
Jul 2015to Jul 2015
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 20Show fewer
  • 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
  • Life expectancy >= 3 months
  • Ability and willingness to give informed consent
  • Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL (milli-International units per milliliter) within 10-14 days prior to and again within 24 hours of starting PF-03084014 and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable barrier methods of birth control AT THE SAME TIME, at least 28 days before she starts taking PF-03084014, during receipt of PF-03084014, and 6 months after discontinuation of PF-03084014; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy
  • A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or a bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
  • Participants must, in the opinion of the investigator, be capable of complying with the protocol

Who cannot join

  • 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
Show all 15Show fewer
  • 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

About this study

Official title: A Phase II Study of Gamma Secretase Inhibitor PF-03084014 in Patients With AIDS-Associated Kaposi Sarcoma

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. Evaluate the tolerance and clinical response of Kaposi sarcoma (KS) tumors to PF-03084014 (gamma secretase inhibitor PF-03084014) with assessments of partial response (PR) and complete response (CR).

SECONDARY OBJECTIVES:

  1. Assess the effect of PF-03084014 on human immunodeficiency virus (HIV) viral load in plasma and the effect of PF-03084014 on cluster of differentiation (CD)4+ cell number.

II. Assess the effect of PF-030840414 in peripheral blood mononuclear cells (PBMCs) and tumors on Kaposi's sarcoma-associated herpesvirus (KSHV) latent and lytic gene expression.

III. Assess effects of PF-03084014 on activation of Notch target genes including tumor-associated endothelial-mesenchymal transition and cell proliferation markers.

IV. Assess effects of trough PF-03084014 drug levels on clinical response and toxicity.

OUTLINE:

Patients receive gamma secretase inhibitor PF-03084014 orally (PO) twice daily (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 stable disease (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.

After completion of study treatment, patients are followed up at 28 days.

Being tested
gamma secretase inhibitor PF-03084014, pharmacological study, laboratory biomarker analysis
Medical subject headings
AIDS-related Kaposi sarcoma, HIV Infections, Sarcoma, Kaposi

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • gamma secretase inhibitor PF-03084014Drug

    Also called PF-03084014

    Given PO

  • pharmacological studyOther

    Also called pharmacological studies

    Correlative studies

  • laboratory biomarker analysisOther

    Correlative studies

Study groups in NCT02137564
Study groupRoleWhat they receive
Treatment (gamma secretase inhibitor PF-03084014)ExperimentalPatients 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.
Receives: Drug: gamma secretase inhibitor PF-03084014; Other: pharmacological study; Other: laboratory biomarker analysis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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).

    Measured: Up to 28 days after completion of study treatment

  2. 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.

    Measured: Up to 28 days after completion of study treatment

Secondary outcomes (5)

  1. Levels of HIV virus load in plasma

    The log10 of the level measured at the end of therapy and the log10 of the level obtained at baseline will be calculated for each patient. Descriptive statistics (e.g., mean, standard deviation, minimum and maximum) will be calculated. If sufficient data are available, a paired t-test will be used to test the log10 virus load difference between the end of therapy and baseline.

    Measured: Up to 168 days

  2. CD4+ cell number

    The log10 of the level measured at day 22, at the end of therapy, and baseline will be calculated for each patient. Descriptive statistics (e.g., mean, standard deviation, minimum and maximum) will be calculated. If sufficient data are available, a paired t-test will be used to test the log10 CD4+ cell number difference between the end of therapy and baseline.

    Measured: Up to day 168 days

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

    Latent and lytic gene expression values will be computed compared to housekeeping genes (e.g. glyceraldehyde-3-phosphate dehydrogenase [GAPDH]), and the ratio of values for each gene at day 8 compared to that at baseline computed for each patient. The median and range will be determined for these ratios. Wilcoxon signed rank test will be used to determine if the ratio is significantly different from 1.0.

    Measured: Baseline to up to day 8

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

    Levels of expression of each gene at baseline and day 8 will be computed compared to housekeeping genes (e.g. GAPDH), and the ratio of values for each gene at day 8 compared to that at baseline computed for each patient. The median and range will be determined for these ratios. Wilcoxon signed rank test will be used to determine if the ratio is significantly different from 1.0.

    Measured: Baseline to up to day 8

  5. Trough gamma secretase inhibitor PF-03084014 drug levels

    Analysis of variance will be used to assess the relationship between trough drug levels and the likelihood of response, the response duration, and time to progression. Analysis of variance will be used to assess the relationship between trough drug levels and the likelihood of grade 3 or higher toxicity.

    Measured: Up to day 22

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 May 2014 (estimated)
  2. Study startJul 2015
  3. Primary completionJul 2015
  4. Study completionJul 2015

Why it stopped: Drug supply unavailable

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02137564
Sponsor's protocol ID
AMC-089
Other IDs
NCI-2014-00638, AMC-089, AMC-089, U01CA121947
Status last verified
Jul 2015
First submitted
9 May 2014
Last updated
23 Jul 2015
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing gamma secretase inhibitor PF-03084014, pharmacological study and laboratory biomarker analysis in people with AIDS-related Kaposi Sarcoma and HIV Infection, run by AIDS Malignancy Consortium.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 23 Jul 2015. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall clinical response (PR and CR) (time frame: Up to 28 days after completion of study treatment). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02137564.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2015.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in