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T. Takahashi
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MINI 07 - ChemoRT and Translational Science (ID 110)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:D. Raben, B. Kavanagh
- Coordinates: 9/07/2015, 16:45 - 18:15, 201+203
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MINI07.01 - A Randomized Phase II Study of S-1 and Cisplatin vs Vinorelbine and Cisplatin with Concurrent Radiotherapy for Locally Advanced NSCLC: WJOG5008L (ID 544)
16:45 - 18:15 | Author(s): T. Takahashi
- Abstract
- Presentation
Background:
Cisplatin-based chemotherapy and concurrent radiotherapy is the standard treatments for locally advanced non-small cell lung cancer ( LA-NSCLC). This trial evaluated two experimental regimens of chemotherapy with concurrent radiotherapy.
Methods:
Eligible patients (pts) with unresectable stage III NSCLC, 20 to 74 years of age, and ECOG PS of 0–1 were randomized to either Arm SP, S-1 (40 mg/m[2]/dose per oral, b.i.d, on days 1-14) and cisplatin (60 mg/m[2] on day 1) repeated every 4 weeks or Arm VP, vinorelbine ( 20mg/m[2] on day 1, 8) and cisplatin (80 mg/m[2] on day) repeated every 4 weeks with early concurrent thoracic radiotherapy of 60Gy at 2 Gy per daily fraction. The primary endpoint was overall survival rate at 2-year (2yr-OS). A pick-the-winner design was used to identify the treatment regimen most likely to be superior. The planned sample size was 55 patients per arm, assuming in each arm that the null hypothesis for 2yr- OS was 50% versus an alternative hypothesis for 65% with one-sided alpha of 0.10 and power of 80%. All the radiation treatment plans were reviewed at quality assurance committee meetings. (Study ID: UMIN000002420)
Results:
One hundred eleven patients were registered between Sep 2009 and Sep 2012. Of 108 patients for efficacy analysis, the 2yr-OS was 76% (95% CI, 62-85%) for SP and 69% (95% CI, 54-79%) for VP. The hazard ratio (HR) of death between the two arms was 0.85 (0.48-1.49). The median progression-free survival (PFS) was 14.8 months for SP and 12.3 months for VP with a HR of 0.92 (0.58-1.44). 80% and 48% of pts completed the protocol treatment in SP and VP, respectively. Common grade 3-4 toxicities of both SP and VP were neutropenia 33%, 75%, platelets 9%, 4%, hemoglobin 26%, 28%, febrile neutropenia 9%, 17%, diarrhea 6%, 0% respectively. There were 4 and 5 treatment-related deaths in Arms SP and VP, respectively. The quality assurance committee judged that 74% of radiation treatment plans had no deviation and 24% had a minor deviation.
Conclusion:
Both arms rejected the null hypothesis for 2yr-OS. In this study Arm SP was declared the winner in terms of 2yr-OS, PFS, treatment completion, and toxicity.
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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Crinò, C.P. Belani
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI15.01 - A Phase I/II Study Evaluating the Combination of Resminostat and Docetaxel for Platinum-Pretreated NSCLC (ID 700)
16:45 - 18:15 | Author(s): T. Takahashi
- Abstract
- Presentation
Background:
Resminostat, an oral hydroxamate-type inhibitor of class I and II histone deacetylases, has shown a broad spectrum of anti-tumor activity against human cancer cell lines, and synergetic or additive effects in combination with docetaxel in non-small cell lung cancer (NSCLC) cell lines. We initiated a phase I/II study to evaluate the safety and efficacy of combining resminostat and docetaxel in patients (pts) with NSCLC pretreated with platinum-based therapy. The purpose of the phase I portion was to evaluate dose-limiting toxicities (DLTs) in the first cycle, estimate the maximum tolerated dose (MTD) of resminostat when administered in combination with docetaxel, and determine the recommended dose (RD) for the phase II portion. Here, we report the results of the phase I portion.
Methods:
NSCLC pts with failure of a platinum-based therapy were eligible for the study. Patients were treated with docetaxel on day 1 and resminostat on days 1 to 5 every 21 days. Phase I was an open-label, 3+3 cohort, dose-escalation study. While the docetaxel dose was fixed at 75 mg/m[2], the resminostat dose was escalated from 400mg (Dose Level 1: DL1) to 600 mg (DL2). DLT was defined as follows: grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia lasting >3 days, and any other clinically significant grade 3/4 non-hematological toxicity.
Results:
A total of 9 pts (DL1: 3 pts, DL2: 6 pts) were enrolled in the phase I portion: male/female, 6/3; median age, 60 yr (50-71 yr); histologically proven adenocarcinoma/squamous cell carcinoma, 7/2; performance status, 0/1 in 7/2 pts. No DLTs were observed at DL1 or DL2. The most frequent grade 3/4 adverse events in any cycle were neutropenia (8 pts, 88.9%), leukocytopenia (8 pts, 88.9%), and febrile neutropenia (4 pts, 44.4%). These events were transient and resolved prior to the next cycle. No pharmacokinetic (PK) interaction between resminostat and docetaxel was observed. A partial response was observed in 1 pts (DL1) and stable disease in 3 pts (DL2).DL1 N=3 DL2 N=6 PK parameters (Geometric Mean) Resminostat Docetaxel Resminostat Docetaxel C~max ~(ng/mL) 3,010 2,840 5,610 3,140 T~max ~(h) 1.78 1.00 1.47 1.03 AUC~inf~(h∙ng/mL) 11,800 3,030 25,500 3,280 t~1/2~ (h) 2.98 8.21 3.02 8.73
Conclusion:
The combination of resminostat and docetaxel was tolerable up to DL2 (docetaxel 75 mg/m[2], resminostat 600 mg); the MTD was not reached. Dose Level 2 was determined as the RD for the phase II portion of this study, which is currently ongoing.
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MINI 37 - SCLC Therapy (ID 165)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:D. Ettinger, G.R. Simon
- Coordinates: 9/09/2015, 18:30 - 20:00, 605+607
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MINI37.06 - Randomized Phase II Trial of CODE or Amrubicin Plus Cisplatin Chemotherapy after Chemoradiotherapy for Limited-Disease Small Cell Lung Cancer (ID 1033)
18:30 - 20:00 | Author(s): T. Takahashi
- Abstract
- Presentation
Background:
Four cycles of etoposide plus cisplatin (EP) concurrently with accelerated hyperfractionation thoracic radiotherapy (AHTRT) is the standard treatment for limited-disease small cell lung cancer (LD-SCLC). The objectives of this study were to evaluate efficacy and toxicities of CODE or amrubicin plus cisplatin (AP) chemotherapy following one cycle of EP and AHTRT in patients with LD-SCLC, and to select the promising arm for subsequent phase III trials.
Methods:
Eligibility criteria included patients with previously untreated LD-SCLC with measurable lesion, ECOG PS of 0-1, and 20-70 years of age. Eligible patients received one cycle of EP (etoposide 100 mg/m[2] on days 1-3 and cisplatin 80mg/m[2] on day 1) plus AHTRT (45Gy/ 30 fractions in 3 weeks). Patients who achieved CR, PR or SD were secondarily registered and randomized to receive either 3 cycles of CODE (cisplatin 25 mg/m[2] on days 1 and 8, doxorubicin 40 mg/m[2] on day 1, etoposide 80 mg/m[2] on days 1-3, and vincristine 1 mg/m[2] on 8 every 2 weeks) or 3 cycles of AP (amrubicin 40 mg/m[2] on days 1-3 and cisplatin 60 mg/m[2] on day 1 every 3 weeks). G-CSF was administered on the days when chemotherapy was not administered in CODE, or on day 5 to the day when a neutrophil count exceeded 5,000/µL in AP. Patients with CR after CODE or AP received prophylactic cranial irradiation. The primary endpoint was the one-year progression-free survival (PFS) after the second registration. Tumor responses were assessed with RECIST version 1.1 by the central review committee. A better regimen for phase III trial is determined with a randomized phase II selection design. The sample size was 72 randomized patients to detect >= 10% difference in one-year PFS with a probability of 80%.
Results:
From May 2011 to Jan 2014, 85 patients from 28 institutions were registered. After the induction EP plus AHTRT, 75 patients were randomized to CODE (n=39) or AP (n=36). Patient demographics were well balanced between the arms. One patient did not receive CODE and 34 (89%) of the 38 patients received 3 cycles of CODE, whereas 33 (92%) of the 36 patients received 3 cycles of AP. Grade 4 neutropenia, anemia and thrombocytopenia were observed in 47%, 21% and 16% of patients in CODE, and in 78%, 6% and 17% of patients in AP, respectively. Grade 3 non-hematological toxicities with the incidence of 5% or higher included febrile neutropenia (16%), hyponatremia (8%), hypokalemia (5%), fatigue (5%), and anorexia (5%) in CODE, and febrile neutropenia (42%), nausea (11%), anorexia (11%), fatigue (8%), esophagitis (6%) in AP. CR and PR were noted in 13 and 25 patients in CODE, and in 10 and 24 patients in AP, respectively. The median overall survival in the 74 patients was 42.8 months. The one-year PFS (95% CI) was 41.0 (25.7 - 55.8) % in CODE and 54.3 (36.6 - 69.0) % in AP.
Conclusion:
The one-year PFS seemed better in AP than in CODE. AP arm is considered to be the test regimen for the subsequent phase III trial.
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