Study of Hsp90 Inhibitor, STA-9090 for Relapsed or Refractory Small Cell Lung Cancer

• To determine response rate using radiologic assessment according to standard RECIST 1.1 criteria [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To determine median progression free survival and overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To evaluate safety and tolerability of of STA-9090 in patients with SCLC [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

• To determine response rate using radiologic assessment according to standard RECIST 1.1 criteria [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To determine median progression free survival and overall survival [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• To characterize the toxicity profile of STA-9090 in this patient population [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

STA-9090 blocks Heat Shock Protein-09 (Hsp90), which is thought to be involved in regulating apoptosis or cell death in small cell lung cancer.

In this research study, the investigators will look to see if STA-9090 has a therapeutic effect on small cell lung cancer. The investigators will also study the safety of STA-9090 and whether measuring circulating tumor cells may help in assessing response to treatment.

Small cell lung cancer (SCLC) is a chemotherapy and radiotherapy sensitive tumor, but with very high rates of relapse and metastasis, resulting in a very poor outcome. Among limited-stage patients, the relapse rate is at least 80% and among extensive-stage patients, the relapse rate is 95-98%. The impetus to develop more effective therapies against novel targets in SCLC is therefore high. Hsp-90 inhibitors are a new class of drugs with important anti-malignant potential in a variety of tumor types because of the reliance of multiple oncoproteins on Hsp90 function.

Although small cell neuroendocrine tumors generally carry many mutated oncoproteins, without clearly defined clients for Hsp90 mediating inhibitor effects in these cells, a recent study demonstrated that Hsp90 inhibition causes massive apoptosis by activating the intrinsic apoptotic pathway in a number of SCLC cell lines. SCLC is a particularly attractive target for apoptosis inducing drugs because of high growth rates and evidence of molecular alterations affecting apoptotic mechanisms. STA-9090 is a novel, small-molecule inhibitor of Hsp90. Unlike earlier generations of Hsp90 inhibitors, STA-9090 has been shown to be a potent inducer of apoptosis in a variety of cell lines and has anti-tumor activity in multiple types of human xenografts. As was seen with other Hsp90 inhibitors, STA-9090 also induces apoptosis in a number of SCLC cell lines (T. Shimamura and G. Shapiro, personal communication).

Based on the anti-tumor potential seen pre-clinically with Hsp90 inhibition, the potent effects of STA-9090 seen pre-clinically as compared with other inhibitors in the same class, as well as early data suggesting safety and tolerability of this drug in the Phase I setting, we are evaluating the single-agent activity of STA-9090 in a Phase II trial of patients with relapsed or refractory small cell lung cancer.

• Cohort A
  Subjects who have relapsed > 60 days following initial chemotherapy completion
  Intervention: Drug: STA-9090
• Cohort B
  Subjects who did not respond or relapsed </= 60 days from the completion of initial chemotherapy
  Intervention: Drug: STA-9090

Inclusion Criteria:

• Histologically confirmed diagnosis of small cell lung cancer and confirmed progressive disease by radiographic study
• </= 3 prior chemotherapy regimens
• Subjects with brain metastases will be allowed if they have been treated with surgery and/or radiation therapy > 21 days prior, are asymptomatic, and are stable for at least 1 week off steroids
• Must have measurable disease
• >/= 18 years of age
• Life expectancy of greater than 12 weeks
• EGOG performance status 0 or 1
• Lab values must be within limits outlined in the protocol
• Not pregnant or breastfeeding
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
• Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

• Chemotherapy or radiotherapy within 3 weeks or within 5 half-lives of previous therapy
• History of severe allergic or hypersensitivity reactions to taxanes.
• Subjects who have not recovered from adverse events or toxicities due to agents administered more than 4 weeks earlier to a grade 1 or less
• Not receiving any other study agents
• History of or current coronary artery disease, myocardial infarction, angina pectoris, angioplasty or coronary bypass surgery.
• Baseline QTc > 470 msec or previous history of QT prolongation while taking other medications.
• Ventricular ejection fraction of < 55%.
• History or current uncontrolled dysrhythmias, or requirement for antiarrhythmic medications, or Grade 2 or greater left bundle branch block.
• ECG with clinically significant ventricular arrhythmias or ischemia
• Major surgery within 4 weeks of starting treatment
• Poor venous access necessitating use of indwelling catheter for IV therapy
• 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
• History of another malignancy unless disease-free for 3 years and deemed to be at low risk for recurrence

• Massachusetts General Hospital
• Beth Israel Deaconess Medical Center
• Synta Pharmaceuticals Corp.