STA-9090(Ganetespib) in Metastatic Ocular Melanoma

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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.

Official Title
-----------------
A Phase II Study of the HSP Inhibitor STA-9090 in Metastatic Ocular Melanoma

Conditions
-----------------
Ocular Melanoma

Intervention / Treatment
-----------------
* Drug: STA-9090


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed stage IV ocular melanoma ECOG Performance status 0, 1, or 2 18 years of age or older Laboratory values as indicated in the protocol Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation Presence of metastatic disease that would be amenable to the required biopsies At least one site of measurable disease as defined by at least 1cm in greatest dimension. This site must be different from the sites to be used for biopsy. No prior radiation therapy or directed ablation to the site of measurable disease Exclusion Criteria: Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier Major surgery within 4 weeks prior to first dose of STA-9090 Minor surgery within 7 days of first dose of STA-9090 Embolization procedure or ablation procedure to treat tumor within 4 weeks of first dose Participants may not be receiving any other investigational agents Poor venous access for study drug administration unless patient can use silicone based catheters History of brain metastases or of leptomeningeal involvement History of allergic reactions or hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to STA-9090 Baseline QTc > 450 msec or previous history of QT prolongation while taking other medications Ventricular ejection fraction (EF) of 55% or less at baseline Treatment with chronic immunosuppressants Melanoma of cutaneous, mucosal or acral-lentiginous origin or of unknown primary Prior treatment with HSP90 inhibitor Not willing to undergo biopsy before and after treatment Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements Other medications, or severe acute/chronic medical or psychiatric conditions or laboratory abnormality that may increase the risk associated with the study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the participant inappropriate for entry into the study Pregnant or breastfeeding women Individual with a history of a different malignancy are ineligible except for circumstances outlined in the protocol HIV-positive individuals on combination antiretroviral therapy History of or current coronary artery disease, myocardial infarction, angina pectoris, angioplasty or coronary bypass surgery History of or current uncontrolled dysrhythmias, or requirement for antiarrhythmic medication, or Grade 2 or greater left bundle branch block NYHA class II/III/IV congestive heart failure with a history of dyspnea, orthopnea or edema that requires current treatment with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers or diuretics Current or prior radiation therapy to the left hemithorax

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: The original dose (Cohort A) was amended based on phase 1 data for safety. Therefore there are 2 separate arms reported.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STA-9090: Cohort A<br>Cohort A participants received STA-9090 200 mg/m2 given intravenously (IV) over 1 hour once weekly (d1, 8, 15 of a 28 day cycle). Participants were treated until evidence of disease progression, unacceptable toxicity, intercurrent illness or withdrawal. | Drug: STA-9090<br> <br> * Other names: Ganetespib;|
| Experimental: STA-9090: Cohort B<br>Cohort B participants received STA-9090 150 mg/m2 given intravenously over 1 hour (IV) twice weekly (d1, 4, 8, 11, 15, 18 of a 28 day cycle). Participants were treated until evidence of disease progression, unacceptable toxicity, intercurrent illness or withdrawal. | Drug: STA-9090<br> <br> * Other names: Ganetespib;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | Estimated up to 24 hours after administration of STA-9090 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
STA9090, STA-9090, HSP90