AIDS-related Kaposi's Sarcoma Clinical Trial
Official title:
Phase I/II Study of Oral MEK Inhibitor Selumetinib (AZD6244 Hyd-Sulphate) in Combination With Highly Active Anti-Retroviral Therapy (HAART) in AIDS-associated Kaposi's Sarcoma (KS).
Cancer is a leading cause of death in individuals living with human immunodeficiency virus (HIV), and Kaposi's sarcoma (KS) remains the commonest HIV-associated cancer. KS is caused when individuals become infected with both HIV and another virus, Human herpesvirus-8 (HHV-8). Laboratory studies have shown that HHV-8 can stimulate biological pathways within KS lesions which promotes their growth. Selumetinib targets these pathways and may therefore be a useful new therapy for KS. Phase I of this trial aims to identify the best dose for the use of selumetinib and investigate the effects of selumetinib treatment on the anti-viral treatment HIV patients receive to control HIV infection. Phase II of this trial will investigate how well selumetinib works as a treatment for KS at the best dose determined in phase I.
BACKGROUND AND RATIONALE
HIV AND KS
The prevalence of HIV in the United Kingdom (UK) is rising with about 83,000 living with HIV
and 7,000 new cases per annum (pa). At diagnosis a third of patients have severe
immune-suppression with a cluster of differentiation 4 (CD4) positive cell count less than
200/mm3 (HPA, 2009), which is associated with opportunistic infections and an increase in
various tumours. Cancer is a leading cause of death in individuals living with HIV, and KS
remains the commonest AIDS-associated malignancy. In a UK prospective cohort followed in the
Highly Active Anti-Retroviral Therapy (HAART) era, 5.5% of HIV positive patients developed KS
(Stebbing et al., 2006).
KS is associated with co-infection with HIV and human herpesvirus-8 (HHV-8). Patients
typically present with multi-focal cutaneous disease often with associated lymphoedema.
Extra-cutaneous disease commonly involves the gastrointestinal tract, lung, liver and spleen.
For early KS, initiation of HAART may be sufficient to control the disease and radiotherapy
is of benefit for localised disease (Di Lorenzo et al., 2007). Currently the only alternative
for progressive localised disease is cytotoxic chemotherapy.
Cytotoxic chemotherapy with liposomal anthracycline or taxanes, is indicated in patients with
widespread cutaneous KS, extensive oral disease or symptomatic visceral involvement (Bower et
al., 2008). Pegylated liposomal doxorubicin (PLD) 20mg/m2 q 3 weeks as first-line therapy in
combination with HAART is reported to give tumour response in 55% of patients and median
progression free survival (PFS) of 22 weeks (Cooley et al., 2007). Second-line therapy with
low dose paclitaxel (100mg/m2 q 2 weeks) is reported to give a response rate of 56% with
median PFS of 39 weeks (Tulpule et al., 2002). However the majority of patients' progress
despite chemotherapy and new treatment alternatives are required.
JUSTIFICATION FOR DESIGN
Selumetinib has been tested in a number of phase I and phase II trials as both monotherapy
and combined with cytotoxic chemotherapy in patients with advanced solid malignancies. A
toxicity profile and recommended dose has been established in these patients. Selumetinib has
not been tested in combination with HAART. No significant interactions are predicted between
Selumetinib and HAART however a phase I study is required to investigate the pharmacokinetic
effects of combining these drugs. In particular we wish to establish that Selumetinib will
not reduce the efficacy of HAART.
This trial is an open-label multi-centre phase I/II study to investigate the use of
selumetinib as a potential treatment for HIV-associated KS. Phase I is an accelerated dose
finding study with dosing commencing at 1 dose level below that recommended for monotherapy
or in combination with cytotoxic chemotherapy. The aims of phase I are to identify a maximum
tolerated dose (MTD) for selumetinib in patients on HAART whilst proving selumetinib does not
reduce the efficacy of HAART. Phase II aims to provide evidence of the efficacy of
selumetinib as a treatment for KS. Evidence of efficacy will be assessed via objective
response rate to treatment and will be used to develop a protocol for a future randomised
phase II/III study.
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00834457 -
A Pilot Study Of the Effects of Highly Active Antiretroviral Therapy on Kaposi's Sarcoma in Zimbabwe
|
Phase 2/Phase 3 |