STA-9090, a synthetic small molecule, demonstrates significant activity for down-regulating Heat Shock Protein 90 or Hsp90 levels. Hsp90 belongs to a class of molecular chaperone proteins known to be critical regulators of cancer cell proliferation and survival. Preclinical laboratory experiments have shown STA-9090, an Hsp90 inhibitor, could inhibit ocular melanoma cell lines. The primary objective of this trial is to obtain evaluations of STA-9090 efficacy to metastatic ocular melanoma.
Patients with metastatic ocular melanoma have a poor prognosis and very limited standard therapeutic options. The recent discoveries of GNAQ and GNA11 mutations leading to MAPK pathway activation and the over-expression of c-Met generate the hypothesis that inhibition of hsp90 client proteins will provide clinical benefit. This study tests the feasibility and efficacy of hsp90 inhibition in patients with metastatic ocular melanoma. Multiple components of the MAPK pathway (B-Raf, C-Raf, cdk4) in addition to c-Met are client proteins of hsp90 and dependent of active hsp90 for stability. Inhibition of hsp90 should lead to decreased expression of these client proteins.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
17
Massachusetts General Hospital
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
4-month Progression Free Survival (PFS) Rate
4-month PFS rate was defined as the proportion of participants alive, absent progression based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST) and on treatment at 4 months. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Relevant for this endpoint was status at 4 months.
Expression of cMET
To estimate the proportion of patients with greater than 50% decrease in expression of HSP90 client protein c-MET 18-24 hours after administration of STA-9090
Time frame: Estimated up to 24 hours after administration of STA-9090
Objective Response Rate (ORR)
ORR is defined as achieving partial response (PR) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR status required confirmation no earlier than 4 weeks following first documentation. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
Time frame: Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Median treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)]. Thus, response on treatment was evaluated up to 31.7 months.
Disease Control Rate (DCR)
DCR is defined as achieving stable disease (SD), partial response (P R) or complete response (CR) based on RECIST 1.0 criteria on treatment. Per RECIST 1.0 for target lesions, CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. CR or PR status required confirmation no earlier than 4 weeks following first documentation. Progressive disease (PD) is at least a 20% increase in the sum LD of target lesions from smallest sum LD as reference or the appearance of one or more new lesions. Stable disease (SD) is neither meeting PR or PD. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions. PR or better response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.
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Time frame: Disease was evaluated radiologically at baseline and every 8 weeks on treatment; Median treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)].Thus, response on treatment was evaluated up to 31.7 months.
Progression-Free Survival (PFS)
PFS based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) requiring removal from the study or death. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Participants who did not experience progression were censored at date of last disease evaluation.
Time frame: Dz was evaluated every 8 weeks on treatment; Imaging was obtained as clinically indicated until off-study; Median (range) on-study duration (months) was cohort A: 8.7 (3.7 to 28.7) and cohort B: 4.5 (1.2 to 36.4 months). Thus, follow-up was up to 36.4m.
Overall Survival (OS)
OS based on the Kaplan-Meier method is defined as the time from study entry to death or date last known alive.
Time frame: Survival follow-up occurred every 4 weeks long-term; Median (range) on-study duration (months) was cohort A: 8.7 (3.7 to 28.7) and cohort B: 4.5 (1.2 to 36.4 months).Thus, follow-up was up to 36.4m.
Grade 3-4 Treatment-Related Toxicity Rate
All grade 3-4 adverse events (AE) with treatment attribution of possibly, probably or definite based on CTCAEv4 as reported on case report forms were counted to calculate the proportion of participants experiencing at least one treatment-related grade 3 or 4 AE of any type on treatment.
Time frame: AE assessment was ongoing from the start of study drug and up to day 30 post-treatment. Mean treatment duration was 1.8 months for each cohort [range: cohort A (0.9-12.5), cohort B (0.8-31.7)). Thus, AEs on treatment were followed up to 31.7 months.