A Phase Ib/II Study of Ganetespib With Doxorubicin in Advanced Solid Tumors Including Relapsed-Refractory Small Cell Lung Cancer.

INTRODUCTION: Small cell lung cancer (SCLC) accounts for 15% of all lung cancers and is characterized by high response rates to cytotoxic chemotherapy and equally high rates of relapse. Many resistance mechanisms have been proposed including resistance to doxorubicin via induction of a heat shock response. Ganetespib is a novel and potent non-geldanamycin heat shock protein 90 (Hsp90) inhibitor. In preclinical studies, synergy between ganetespib and doxorubicin was shown. We conducted a phase Ib/II study of the safety, tolerability, and preliminary efficacy of the combination of ganetespib and doxorubicin. METHODS: Patients eligible for the phase Ib portion had advanced tumors that would be appropriate for doxorubicin therapy and those in the phase II portion had relapsed or refractory SCLC. All patients had an ECOG performance status, 0-1 and adequate organ function, including a cardiac ejection fraction ≥50%. Patients who received a lifetime cumulative doxorubicin dose of >150 mg/m2 or who had symptomatic brain metastases were excluded. Patients received ganetespib on Days 1 and 8 and doxorubicin 50 mg/m2 on day 1 in 21-day cycles. RESULTS: Eleven patients were enrolled including nine in the phase Ib dose escalation and two in the phase II expansion. The study was terminated by the sponsor. The dose recommended for future study is ganetespib 150 mg/m2 in combination with doxorubicin at a dose of 50 mg/m2. The most common adverse events of the combination were grade 1/2 diarrhea, nausea, fatigue, and transaminitis. No dose limiting toxicities were observed. Response rate was 25% and median duration of response was 137 days. CONCLUSION: Ganetespib plus doxorubicin was a well-tolerated combination and there remains potential for the clinical development of Hsp90 inhibitors in SCLC. CLINICAL TRIAL REGISTRATION: https://ClinicalTrials.gov/ct2/show/NCT02261805, identifier NCT02261805.

A phase I study of bendamustine, lenalidomide and rituximab in relapsed and refractory lymphomas.

Many patients with non-Hodgkin (NHL) or Hodgkin lymphoma (HL) relapse or are refractory to initial therapy and require additional options. Bendamustine (B), lenalidomide (L) and rituximab (R) each have activity in this setting. This study was performed to determine the safety of BLR and its optimal phase II dose. Patients with NHL or HL failing standard therapies received B (90 mg/m(2)  days 1, 2 every 28 days), and L (escalating from 5 mg 21/28 days) for six cycles, followed by 6 months of L. At the highest dose R 375 mg/m(2) on day one of each cycle was added for patients with B-NHL. Histologies included diffuse large B-cell lymphoma (DLBCL, 11), marginal zone lymphoma (3), HL (2), and one each of transformed follicular lymphoma, Sézary syndrome, Waldenström macroglobulinaemia and mantle cell lymphoma. Neutropenia was the most common grade 3 and 4 toxicity, but no maximum tolerated dose was identified. Of 20 patients, seven responded (35%), including four complete remissions, with five unmaintained responses from 28+ to 37+ months, including 2 DLBCL. BR with 20 mg l at, 21/28 days achieved durable responses; however, in light of its modest activity, and the availability of newer targeted therapies, the future of BLR is uncertain.

A prospective randomized pilot study to evaluate predictors of response in serial core biopsies to single agent neoadjuvant doxorubicin or paclitaxel for patients with locally advanced breast cancer.

INTRODUCTION: Response to neoadjuvant chemotherapy for locally advanced breast cancer can be correlated with long-term outcomes. Surrogate end-point biomarkers may be used to assess response to the treatment. Most reported studies assessed the effects of combination chemotherapy. We assessed the feasibility of obtaining serial core breast biopsies, and correlated rates of apoptosis, proliferation, and expression of related proteins at baseline, during, and after neoadjuvant single agent chemotherapy for locally advanced breast cancer with response. EXPERIMENTAL DESIGN: Women with a histologically confirmed unresected T(3) or T(4) infiltrating carcinoma of the breast were eligible. The first 20 patients received three cycles of doxorubicin 90 mg/m(2) followed by three cycles of paclitaxel 250 mg/m(2), or the reverse. Nine women received four cycles of each (doxorubicin 60 mg/m(2) and paclitaxel 175 mg/m(2)). Cycles were administered 14 days apart with filgastrim. End points included: (a). clinical and pathological response; (b). serial apoptotic [terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling] and proliferation (immunohistochemistry, IHC) rates; and (c). expression (IHC) of estrogen receptor, HER2, bcl2, and p53. RESULTS: From April 1997 to June 2001, 29 women were randomized. Twelve patients (42%) had a clinical complete response (cCR), and 16 (55%) had a clinical partial response. Five women (17%) had a pathological complete response, 7 (24%) had microscopic residual disease, and 17 (58%) had macroscopic residual disease. Higher baseline apoptosis and proliferation were associated with an improved pathological response (P = 0.006 and 0.003, respectively). Among 14 evaluable patients, apoptosis increased in women who had a cCR to the first agent but not in women without a cCR. Estrogen receptor-positive patients had a worse pathological response (P = 0.004). CONCLUSIONS: The selected regimen is efficacious. It is feasible to obtain serial core biopsies that are informative for studies of apoptosis and IHC. This clinical design can serve as a model for combining standard chemotherapy and novel agents.