Livia Szeto

Phase I Study of G3139, a bcl-2 Antisense Oligonucleotide, Combined With Carboplatin and Etoposide in Patients With Small-Cell Lung Cancer

PURPOSE Bcl-2 is expressed in the majority of cases of small cell lung cancer (SCLC) and may contribute to chemotherapeutic resistance. Bcl-2 suppression by G3139 (oblimersen sodium), a phosphorothioate oligonucleotide complementary to the bcl-2 mRNA, has the potential to enhance the antitumor efficacy of standard cytotoxic chemotherapy. A dose-finding study was performed evaluating the combination of G3139, carboplatin, and etoposide in patients with previously untreated extensive stage SCLC. PATIENTS AND METHODS Sixteen patients were treated in three consecutive cohorts. Cohort 1 (n=5) received G3139 5 mg/kg/d on days 1 to 8 of a 21 day cycle, with carboplatin area under the curve (AUC)=6 on day 6, and etoposide 80 mg/m2/d on days 6 to 8. In cohort 2 (n=4), carboplatin dose was reduced to AUC=5. In cohort 3 (n=7), G3139 dose was escalated to 7 mg/kg/d. G3139 plasma concentrations and Bcl-2 protein levels in peripheral blood mononuclear cells were evaluated. RESULTS Two of three assessable patients in cohort 1 experienced cycle 1 dose-limiting toxicity (grade 4 neutropenia). No cycle 1 dose-limited toxicity was observed in cohorts 2 or 3. Of 14 patients assessable for response, partial response was documented in 12 patients (86%), and stable disease in two. Median time to progression was 5.9 months. Carboplatin and etoposide administration did not appear to alter G3139 pharmacokinetics. No evidence of Bcl-2 suppression in peripheral blood mononuclear cells was observed. CONCLUSION The combination of G3139, carboplatin, and etoposide is well tolerated and results in an encouraging response rate and time to progression in patients with extensive stage SCLC.

Paxillin is a target for somatic mutations in lung cancer: Implications for cell growth and invasion

Lung cancer is characterized by abnormal cell growth and invasion, and the actin cytoskeleton plays a major role in these processes. The focal adhesion protein paxillin is a target of a number of oncogenes involved in key signal transduction and important in cell motility and migration. In lung cancer tissues, we have found that paxillin was highly expressed (compared with normal lung), amplified (12.1%, 8 of 66) and correlated with increased MET and epidermal growth factor receptor (EGFR) gene copy numbers, or mutated (somatic mutation rate of 9.4%, 18 of 191). Paxillin mutations (19 of 21) were clustered between LD motifs 1 and 2 and the LIM domains. The most frequent point mutation (A127T) enhanced lung cancer cell growth, colony formation, focal adhesion formation, and colocalized with Bcl-2 in vitro. Gene silencing from RNA interference of mutant paxillin led to reduction of cell viability. A murine in vivo xenograft model of A127T paxillin showed an increase in tumor growth, cell proliferation, and invasion. These results establish an important role for paxillin in lung cancer.

A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with Locally Advanced or Metastatic Non–Small Cell Lung or Esophageal Cancer

Purpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. Experimental Design: Patients with locally advanced or metastatic non–small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m2); regimen 2 was pemetrexed (500 mg/m2) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m2). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m2; AUC = 6); grade 3/4 leukopenia (4 of 12 patients) was the main hematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed. When systemically active chemotherapy doses were reached, further dose escalation was discontinued, and a phase II dose-range was established (pemetrexed 500 mg/m2 and carboplatin AUC = 5-6). Conclusions: The combination of pemetrexed (500 mg/m2) and carboplatin (AUC = 5 or 6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage III NSCLC.

Phase I Trial of Erlotinib-Based Multimodality Therapy for Inoperable Stage III Non-small Cell Lung Cancer

Introduction: This Phase I trial aimed to determine the maximum-tolerated-dose of erlotinib administered with two standard chemoradiotherapy regimens for non-small cell lung cancer. Methods: Unresectable stage III non-small cell lung cancer patients were enrolled in this 2-arm dose-escalation study. Erlotinib, given only during chemoradiotherapy, was escalated from 50 to 150 mg/d in 3 to 6 patient cohorts. Arm A: erlotinib with cisplatin (50 mg/m2 IV days 1, 8, 29, 36), etoposide (50 mg/m2 IV days 1-5, 29-33) and chest radiotherapy (66 Gy, 2 Gy/d) followed by docetaxel (75 mg/m2 IV Q21 d) for 3 cycles. Arm B: induction carboplatin (AUC 6) and paclitaxel (200 mg/m2) for two 21-d cycles then radiotherapy with erlotinib, carboplatin (AUC = 2/wk) and paclitaxel (50 mg/m2/wk). Results: Seventeen patients were treated in each arm. Patient characteristics: performance status 0 to 24 patients, 1 to 10 patients, median age 63 years, adenocarcinoma 21% and female 14 patients. Dose-escalation of erlotinib to 150 mg/d was possible on both chemoradiotherapy regimens. Grade 3/4 leukopenia and neutropenia were predominant toxicities in both arms. Grade 3 chemoradiotherapy toxicities in arm A were esophagitis (3 patients), vomiting (1), ototoxicity (1), diarrhea (2), dehydration (3), pneumonitis (1); and arm B was esophagitis (6). Seven patients (21%) developed rash (all grade 1/2). Median survival times for patients on Arm A and B were 10.2 and 13.7 months, respectively. Three-year overall survival in patients with and without rash were 53% and 10%, respectively (log-rank P = 0.0807). Epidermal growth factor receptor IHC or FISH positive patients showed no significant overall survival difference. Conclusion: Addition of standard-dose erlotinib to chemoradiotherapy is feasible without evident increase in toxicities. However, the survival data are disappointing in this unselected patient population and does not support further investigation of this approach.

A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest

JM216 is an orally administered platinumanalogue. We undertook this study todetermine the maximally tolerated dose(MTD) of JM216 when administered withconcomitant radiotherapy to the chest(200 cGy daily, 5×/week) in patients withlocoregionally advanced non-small cell lung(NSCLC) or esophageal cancer. Patientswere excluded for inadequate bone marrowreserve, prior radiotherapy to the primarytumor or previous treatment with platinumdrugs. A dose-limiting toxicity (DLT) wasdefined using the National Cancer Institute(NCI) Common Toxicity Criteria (CTC) andconsisted of grade ≥2 renal, hepatic,cardiac, or pulmonary toxicity or grade ≥3hematologic, neurological, orgastrointestinal toxicity. A total of 23patients were registered; two neverreceived treatment and are excluded fromanalyses. Six patients were treated at adose of 30 mg/m2/day for 5 days withtwo grade 2 DLTs: cough (1 pt) andelevated trans-aminases (1 pt). Sevenevaluable patients were treated at60 mg/m2/day and seven experiencedgrade 3 or 4 toxicity, five related tomyelosuppression. The dose was thenreduced to 45 mg/m2/d. Eight patientswere evaluable for toxicity, of which 5experienced DLT: myelosuppression (3 pts),esophagitis (2 pts), dyspnea (1 pt), andelevated creatinine (1 pt). Fourteenpatients were evaluable for efficacy, ofwhich 6 had an objective response,including one complete response. Therecommended phase II dose of JM216 withconcurrent radiation therapy is30 mg/m2/d for 5 days. The major DLTis myelosuppression with only limitedincreased toxicity within the field ofradiation. This conceivably may limit theuse of JM216 as a radiation sensitizer.

Phase II Trial of Temozolomide and Irinotecan as Second-Line Treatment for Advanced Non–small Cell Lung Cancer

Background: This study was performed to evaluate the tolerability and efficacy of temozolomide and irinotecan as a second-line regimen in recurrent/metastatic non–small cell lung cancer (NSCLC). Methods: Patients with recurrent/metastatic NSCLC, including those with treated brain metastases, following one prior platinum-based regimen received temozolomide 75 mg/m2 daily on days 1 through 15 and irinotecan 100 mg/m2 on days 8 and 15 every 21 days. Results: The authors treated 46 patients, of whom more that 90% had a performance status of 0 or 1. Four patients (8.7%) attained partial response and 17 (37.0%) had disease stabilization as their best response. The median time to progression was 1.8 months, median overall survival was 9.8 months, and 1-year overall survival was 34%. Grade 1/2 fatigue (63%), anemia (61%), nausea (52%), and diarrhea (44%) were the most common toxicities. Grade 3/4 leukopenia and diarrhea were each observed in 9% of patients. One unexpected death occurred, possibly related to the regimen. Conclusion: Second-line treatment with temozolomide and irinotecan showed tolerable toxicities. The response rates, median survival times, and 1-year survival rates were comparable to other active NSCLC agents.

Targeted and cytotoxic therapy in coordinated sequence (TACTICS): erlotinib, bevacizumab, and standard chemotherapy for non-small-cell lung cancer, a phase II trial.

BACKGROUND This trial focused on optimally combining existing targeted therapies and cytotoxic chemotherapy in the treatment of unselected patients with advanced non-small-cell lung cancer (NSCLC). METHODS Patients with previously untreated advanced-stage nonsquamous NSCLC were eligible for this trial. In module A, patients received up to 4 cycles of erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients then received carboplatin (AUC = 6), paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg for 4 cycles in module B. Patients who did not have progressive disease in module A received maintenance erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks in module C. RESULTS Forty-eight patients were enrolled in this multicenter phase II trial. Most patients were male (62.5%) and white (77.1%) with stage IV disease (93.8%) and adenocarcinoma histologic type (66.7%). The overall response rate in module A was 10.4%, in module B it was 15.1%, and in module C it was 5.5%. The study achieved its primary endpoint, with a nonprogression rate of 45.8% in module A. The median overall survival (OS) was 12.6 months. CONCLUSION The novel systemic therapy regimen is feasible in patients with advanced NSCLC. However there is no further role for developing this regimen in unselected patients with NSCLC.

Phase I Study of Induction Chemotherapy and Concomitant Chemoradiotherapy with Irinotecan, Carboplatin, and Paclitaxel for Stage III Non-small Cell Lung Cancer

Background: The aim of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and determine the phase II dose for the combination of irinotecan-carboplatin-paclitaxel given as induction chemotherapy and with concomitant chest radiotherapy for patients with Stage III non-small cell lung cancer. Methods: Patients with Cancer and Leukemia Group B performance status of 0 to 2, stage IIIA and IIIB NSCLC patients with resectable or unresectable disease were treated with induction chemotherapy (irinotecan 100 mg/m2, carboplatin AUC 5, and paclitaxel 175 mg/m2 days 1 and 22) followed by concomitant chemotherapy (irinotecan, carboplatin, and paclitaxel) and chest radiotherapy (66 Gy for unresectable and 50 Gy for resectable disease) beginning on week 7. The primary objective was to escalate the dose of irinotecan during chemoradiation in sequential cohorts to determine the DLT and MTD of the regimen. Results: Thirty-eight patients were enrolled (median age 63 years, 57% male, 41% performance status 0, 30% resectable). Induction chemotherapy was tolerable and active (response rate 26%; stable disease 60%). Eight patients did not receive concurrent chemoradiotherapy because of progressive disease (5), death (1), hypersensitivity reaction to paclitaxel (1), and withdrawal of consent (1). Twenty-nine patients received concurrent chemoradiotherapy. The concomitant administration of chest radiotherapy with weekly irinotecan, carboplatin, and paclitaxel was not feasible at the first, second, and third dose levels. DLT was failure to achieve recovery to ≤ grade 1 absolute neutrophil count by the day of scheduled chemotherapy administration. Dose de-escalation to irinotecan 30 mg/m2, paclitaxel 40 mg/m2 (with omission of carboplatin) delivered on weeks 2, 3, 5, and 6 of radiotherapy was the MTD. After induction chemotherapy, partial responses, stable disease, and progressive disease was observed in 26%, 60%, and 14% of patients, respectively. After chemoradiotherapy, partial responses were attained in 16 (55%) patients, whereas 12 patients (41%) attained disease stabilization. Median overall survival was 21 months for the entire cohort. Resectable patients had a median survival of 24 months, whereas unresectable patients had a median survival of 19 months. Differences in overall and progression-free survival rates between resectable and unresectable patients was not statistically significant (p = 0.52 and p = 0.90, respectively). Discussion: Carboplatin, paclitaxel, and irinotecan with concurrent chemoradiotherapy was poorly tolerated as a result of neutropenia. Although dose de-escalation was required for delivery of the regimen, the response rates and survival outcomes were comparable to other similar regimens.

Sustained Oligoclonal T Cell Expansion Correlates with Durable Response to Immune Checkpoint Blockade in Lung Cancer

Purpose: Antibodies that target immune checkpoint molecules have demonstrated significant and durable clinical benefit through re-activation and proliferation of pre-existing tumor-infiltrating CD8+ T cells in a broad range of tumor types including lung cancer. Detailed characterization of T cell dynamics at clonal levels using nextgeneration T cell receptor (TCR) sequencing in large cohorts of lung cancer patients is yet reported.Methods: We performed TCR sequencing of peripheral blood samples (and some tumors) obtained from 27 lung cancer patients undergoing single/combined immune checkpoint blockade therapies.Results: In one responder, we found expansion of a single T cell clone (approximately 20% of the all TCR reads) in a metastatic subcutaneous lesion that showed pathologic complete response on day 17 of treatment. The same TCR CDR3 sequence was detected in 6.1% of TCR reads in the peripheral blood prior to treatment initiation and the expansion remained persistent in peripheral blood at 21.0% at week 10 and 24.3% at week 48. In other patients who showed durable response, we also found persistent oligoclonal T cell expansion in their peripheral blood which was not observed in non-responders even while they remained on therapy.Conclusion: We found sustained expansion of oligoclonal T cell clones in lung cancer patients who had durable response to immune checkpoint blockade. This suggests possible use of longitudinal TCR sequencing to assist clinical decision-making, assess synergism with other agents, and most importantly facilitate rational development of alternative treatment strategies for non-responders.

A phase I study of induction chemotherapy (CT) and concomitant chemoradiotherapy (CRT) with carboplatin (C), paclitaxel (P), and irinotecan (I) for stage III non-small cell lung cancer (NSCLC)

7170 Background: A standard therapy for unresectable stage III NSCLC includes CT with P & C followed by concomitant P & C with radiotherapy (RT) (CALGB 39801). Preclinical data indicates synergy between I & C and I & P. Their combined administration might result in a further increase of antitumor activity. Preclinical data also suggests RT enhancement by each of the 3 drugs. This phase I study evaluated a regimen of CT with IPC followed by CRT with IPC in patients (pts) with stage III NSCLC. METHODS The CT regimen (JCO 19:2001, 1078) consisted of two 21-day cycles of I (100mg/m2 on d1), P (175 mg/m2 on d1) & C (AUC=5 on d1). During XRT (50 Gy for resectable and 66 Gy for unresectable) pts received weekly chemotherapy of I, P, & C in sequential cohorts of dose levels (Table 1). Accrual to dose level IV has been completed. Eligibility criteria included CALGB performance status (PS) ≤2 and stage III NSCLC without prior CT or RT. RESULTS 38 pts were enrolled with median age 63; PS 0/1/2 in 15/19/4. Toxicity during CT included grade 3/4 neutropenia (17); grade 3 hemoglobin (1); grade 3 diarrhea (1); neutropenic fever (2); neutropenic infection (1). 3 pts had distant progression & 3 pts had local progression during CT. 26 pts have been evaluated for CRT. Dose-limiting toxicities (DLTs) for CRT were grade 3 neutropenia > 1 wk: dose I (3/75%), II (3/50%), III (2/18%). Other toxiticites: grade 3 esophagitis in 12/26 pts & grade 3 radiation pneumonitis in 1 pt in dose II. The regimen demonstrated significant activity with 14 pts having partial response after CT + CRT. 6 pts had surgical resection after CRT & 2 pts had a complete response. CONCLUSIONS DLT is neutropenia of duration > 1 wk. Dose level IV is currently under evaluation and is likely the maximally tolerated dose of I & P that can be administered with CRT. [Figure: see text] [Table: see text].