A randomized, phase II efficacy assessment of multiple MET kinase inhibitors in metastatic papillary renal carcinoma (PRCC): SWOG S1500.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4599-TPS4599 ◽  
Author(s):  
Sumanta K. Pal ◽  
Catherine M. Tangen ◽  
Ian Murchie Thompson ◽  
Brian M. Shuch ◽  
Naomi B. Haas ◽  
...  
Keyword(s):  
Phase Ii ◽  
Metastatic Disease ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Performance Status ◽  
Progression Free Survival ◽  
Type I ◽  
Type Ii ◽  
Randomized Phase Ii ◽  
Clear Cell Rcc

TPS4599 Background: PRCC constitutes approximately 15% of RCC cases, and no standard of care exists for metastatic disease. Approved VEGF- and mTOR-directed therapies for clear cell RCC in metastatic PRCC (mPRCC) have generally been ineffective. Trials assessing sunitinib and everolimus in non-clear cell RCC show a numerical advantage in progression-free survival (PFS) with sunitinib therapy. Prospective studies evaluating sunitinib in mPRCC show a broad range of efficacy, with PFS ranging from 1.6-6.6 months. Another possible approach to treating mPRCC is to target the MET protooncogene, which is frequently altered across both type I and type II disease. SWOG 1500 is a randomized, phase II study which will compare sunitinib to three MET-directed therapies in pts with mPRCC. Methods: Eligible pts will have PRCC (type I, type II or NOS), Zubrod performance status 0-1, and measurable metastatic disease. Pts may have received up to 1 prior systemic therapy, with the exception of prior VEGF-directed treatments. Treated brain metastases are allowed. Tissue must be available for central pathologic review of papillary subtype. Pts will receive either oral sunitinib, cabozantinib, crizotinib or savolitinib in a 1:1:1:1 randomization, with stratification by (1) prior therapy (0 vs 1) and (2) PRCC subtype (type I vs type II vs NOS). The primary endpoint of the study is to compare PFS with sunitinib to PFS with MET-directed therapies. Secondary endpoints in the study include comparison of response rate, overall survival and safety profile. Translational aims of the study include correlation of clinical outcome with MET mutation, copy number and other markers of MET signaling. Radiographic assessment will be performed every 12 wks. Interim analyses are planned for each arm. A total of 275 pts will be enrolled, with 26 pts registered as of Jan 30, 2017. Clinical trial information: NCT02761057.

Sunitinib versus cabozantinib, crizotinib or savolitinib in metastatic papillary renal cell carcinoma (pRCC): Results from the randomized phase II SWOG 1500 study.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 270-270
Author(s):  
Sumanta K. Pal ◽  
Catherine Tangen ◽  
Ian Murchie Thompson ◽  
Naomi B. Haas ◽  
Daniel J. George ◽  
...  
Keyword(s):  
Overall Survival ◽  
Kinase Inhibitors ◽  
Performance Status ◽  
Progression Free Survival ◽  
Papillary Renal Cell Carcinoma ◽  
Primary Objective ◽  
Type I ◽  
Type Ii ◽  
Prior Therapy ◽  
Intent To Treat

270 Background: MET signaling is a key molecular driver in pRCC. Given that there is no optimal therapy for metastatic pRCC, we sought to compare an existing standard (sunitinib) to putative MET kinase inhibitors. Methods: Eligible patients had pathologically verified pRCC, Zubrod performance status 0-1, and measurable metastatic disease. Patients may have received up to 1 prior systemic therapy excluding VEGF-directed agents. Patients were randomized 1:1:1:1 to receive either sunitinib 50 mg po qd (4 wks on/2 wks off), cabozantinib 60 mg po qd, crizotinib 250 mg po bid, or savolitinib 600 mg po qd. Patients were stratified by prior therapy and pRCC subtype (I vs II vs not otherwise specified [NOS]) based on local review. The primary objective was to compare progression-free survival (PFS) for each experimental arm versus sunitinib. With 41 eligible patients per arm, we estimated 85% power to detect a 75% improvement in median PFS with a 1-sided alpha of 0.10 using intent-to-treat analysis. A pre-planned futility analysis was performed after 50% of PFS events occurred. Secondary endpoints included toxicity, response rate, and overall survival. Results: Between 4/2016 and 12/2019, 152 patients were enrolled; 5 were ineligible. Median age was 66 (range:29-89) and 76% were male; 92% had no prior therapy. By local pathologic review, 18%, 54% and 28% of patients were characterized as having type I, type II and NOS histology, respectively. In contrast, the frequency of type I, type II, and NOS by central review was 30%, 45% and 25%, respectively. Accrual to the savolitinib and crizotinib arms was halted early for futility (PFS hazard ratio > 1.0 for both); accrual continued to completion in the sunitinib and cabozantinib arms. Median PFS was significantly higher with cabozantinib relative to sunitinib (Table). Grade 3 or 4 adverse events occurred in 69%, 72%, 37% and 39% of patients receiving sunitinib, cabozantinib, crizotinib and savolitinib, respectively; one grade 5 adverse event was seen with cabozantinib. Overall survival and response data will be presented. Conclusions: In this multi-arm randomized trial, only cabozantinib resulted in a statistically significant and clinically meaningful prolongation of PFS in pRCC patients compared to sunitinib. These data support cabozantinib as a reference standard for eligible patients with metastatic pRCC. Clinical trial information: NCT02761057 . [Table: see text]

Denosumab and pembrolizumab in clear cell renal carcinoma (KEYPAD): A phase II trial (ANZUP1601).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS367-TPS367
Author(s):  
Craig Gedye ◽  
Abhishek Jagdish Joshi ◽  
Alison Yan Zhang ◽  
Andrew James Martin ◽  
Anthony M. Joshua ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Phase Ii Trial ◽  
Case Reports ◽  
Cell Cancer ◽  
Tumour Response ◽  
Predictive Biomarkers ◽  
Progression Free Survival

TPS367 Background: Inhibitors of the programmed death-1 pathway (PD-1) are effective in clear cell renal cell cancer (ccRCC). Preclinical data and case reports suggest that denosumab, an inhibitor of Receptor Activator of Nuclear Factor κ-B Ligand (RANKL) signaling, could potentiate the anti-tumour effects of anti-PD1 inhibitors without overlapping toxicities. We aim to determine the activity and safety of combining denosumab and pembrolizumab in advanced ccRCC. Methods: This single arm, multi-center, phase II trial will recruit 70 participants with metastatic or unresectable ccRCC, progressing during or after treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, and with no prior treatment with immunotherapy or denosumab. Participants will receive pembrolizumab 200mg IV every 3 weeks plus denosumab 120mg SC on days 1, 8 and 22 and then every 3 weeks until disease progression, prohibitive toxicity or maximum treatment of 24 months. Response will be assessed at weeks 12, 18, 24, then every 12 weeks until disease progression. Bloods for translational studies are collected at baseline, week 6 and on disease progression. The primary endpoint is objective tumour response rate (OTRR) per RECIST 1.1. Secondary endpoints include OTRR per iRECIST, progression free survival (PFS), time to OTRR, time to first skeletal related event, adverse events, and frequency of treatment delays/discontinuations. Correlative studies will include identification of prognostic and/or predictive biomarkers relating to immune and RANKL signaling. A sample size of 70 provides 90% power with a 1-sided type 1 error rate of 10% to distinguish the observed OTRR (and PFS at 6 months) from an OTRR of 40% (worthy of pursuit) versus 25% (not worthy of pursuit). 15 sites are open across Australia. As of September 23, 2020, 40 patients have been recruited. Clinical trial information: NCT03280667 .

A randomized phase II trial of weekly docetaxel plus either cisplatin or oxaliplatin in patients with previously untreated advanced gastric cancer: Preliminary results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4566-4566
Author(s):  
S. Sym ◽  
S. Park ◽  
J. Park ◽  
K. Kwon ◽  
I. Jung ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Tolerability Profile ◽  
Preliminary Results ◽  
Weekly Docetaxel ◽  
Randomized Phase Ii ◽  
Significant Difference

4566 Background: Docetaxel, in combination with cisplatin or oxaliplatin, has demonstrated efficacy against AGC. This randomized phase II trial evaluated two weekly docetaxel-based regimens to see which would be most promising according to objective response rate (ORR) as first-line therapy in AGC. Methods: Chemotherapy-naïve patients with measurable unresectable and/or metastatic gastric adenocarcinoma and a performance status ≤2 were randomly assigned to receive docetaxel (35 mg/m2) weekly on days 1 and 8 of a 21-day cycle plus either cisplatin (60 mg/m2 on day 1) (arm A) or oxaliplatin (120 mg/m2 on day 1) (arm B). Toxicity was assessed on days 1, 8, and 21 of each cycle, and response was evaluated every 2 cycles. Results: Between March 2007 and December 2008, 61 eligible patients entered. In Arm A, 29 patients were evaluable for objective response and 31 for safety. In Arm B, 28 patients were evaluable for objective response and 30 for safety. Median age was 52 years and disease status was comparable for both arms. Ten of 29 (34.5%) patients had a confirmed objective response in the arm A (95% confidence interval [CI] 17.1–51.8%) and 11 of 28 (39.2%) patients had a confirmed objective response in the arm B (95% CI 21.1- 57.2%). No significant difference was noted between the arms both for ORR (p=0.202) or for disease control (58.6% and 82.1%, respectively, p=0.082). Median progression free survival time was 4.4 month in the arm A and 4.3 months in the arm B (Hazard ratio = 0.936; 95% CI, 0.503–1.744; p = 0.836). There was no relevant difference in the occurrence of overall grade ¾ toxicity between the two arms (51.6% vs. 46.6%, respectively; p=0.800). Neutropenia was the most common grade 3/4 toxicity (32.3% vs. 36.6%, respectively). There was one treatment related death in Arm B. Conclusions: The preliminary results showed that both treatment arms have similar clinical efficacy as front-line treatment in AGC. Each regimen has a manageable tolerability profile. The accrual is ongoing. No significant financial relationships to disclose.

Randomized phase II study of pharmacodynamic separation (PDS) of pemetrexed (Pem) and erlotinib (Erl) versus pem alone in patients (pts) with advanced non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8097-8097 ◽  
Author(s):  
Tianhong Li ◽  
Bilal Piperdi ◽  
William Vincent Walsh ◽  
Mimi Kim ◽  
Rasim Gucalp ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Performance Status ◽  
Progression Free Survival ◽  
Dose Schedule ◽  
Phase Iii ◽  
Smoking History ◽  
Clinical Activity ◽  
P Value ◽  
Randomized Phase Ii

8097 Background: Preclinical and phase I studies showed that PDS optimizes cytotoxicity of concurrent EGFR inhibitors and chemotherapy. We conducted a randomized phase II trial to assess relative efficacy of Pem alone (Arm A) versus Pem +Erl on a PDS dose-schedule (Arm B) as 2nd-line therapy in pts with advanced NSCLC (NCT00950365). Methods: Eligible pts were randomized 2:1 (Arm B: A), stratified by sex, smoking history, and performance status (0/1 vs 2). Accrual was restricted to non-squamous histology in 2009. Treatment: Arm A – Pem 500 mg/m2IV on day 1; Arm B – Pem + Erl 150 mg po QD on days 2-17. 1 cycle = 3 weeks. Primary endpoint was progression-free survival (PFS). 50 pts in Arm B were needed to detect an increase in median PFS from ~3 to 4.5 months. Results: 83 pts were entered. Age: 63 yo. Female: 42 (53%). Smoking ≥15PY: 58 (72%). Nonsquamous: 78 (99%). The primary endpoint of the study was met: Efficacy results from 79 eligible pts showed 1.6-fold longer PFS in Arm B (4.6 m) compared to Arm A (2.8 m). Although the study was not designed to directly compare two arms, p value was 0.052. Toxicity: G3/4 Hem (A/B): 8(30%)/12(23%); Neutropenia with infection (A/B): 0/3(6%). G3/4 Non-Hem (A/B): skin rash: 0/3(6%); diarrhea: 0/2(4%); joint pain: 1(4%)/6(11.5%). Treatment related death (A/B): 0/1. Interstitial lung disease (A/B): 0/1. Conclusions: PDS of Pem and Erl is well tolerated and has promising clinical activity in 2nd-line non-squamous NSCLC. Ongoing correlative studies aim to identify a subgroup of patients who might benefit most from this treatment, which will guide the design of a confirmatory phase III study. (UL1 RR024146, P30CA093373, Lilly, Astellas) Clinical trial information: NCT00950365. [Table: see text]

Palbociclib plus cetuximab versus placebo plus cetuximab in platinum-resistant, cetuximab-naive, HPV-unrelated head and neck cancer: A double-blind randomized phase II trial (PALATINUS).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6013-6013 ◽  
Author(s):  
Douglas Adkins ◽  
Jin-Ching Lin ◽  
Assuntina Gesualda Sacco ◽  
Jessica C. Ley ◽  
Peter Oppelt ◽  
...  
Keyword(s):  
Head And Neck ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Rank Test ◽  
Double Blind ◽  
Platinum Resistant ◽  
Randomized Phase Ii

6013 Background: Cetuximab monotherapy results in a median overall survival (OS) of approximately 6 months (mo) in platinum-resistant recurrent/metastatic head and neck squamous cell carcinoma (HNSCC). HNSCC unrelated to human papillomavirus (HPV) is driven by hyperactivation of the CDK4/6 and cyclin D1 (CD1) regulatory complex, resulting in cell cycle progression and tumor growth, suggesting that CDK4/6 inhibition can be a rational therapeutic strategy in this setting. Palbociclib (PAL) is a selective CDK4/6 inhibitor that may reverse cetuximab resistance by countering the actions of deregulated CD1. PAL plus an epidermal growth factor receptor inhibitor synergistically reduced cell viability of HPV-unrelated HNSCC cell lines. In a single-arm, multicenter trial of platinum-resistant, cetuximab-naive, HPV-unrelated HNSCC, PAL in combination with cetuximab resulted in a median OS of 9.5 mo. Methods: In a double-blind randomized phase II trial, patients (pts) with platinum-resistant, cetuximab-naïve, HPV-unrelated HNSCC were treated with cetuximab plus either PAL (arm A) or placebo (arm B). Pts were stratified by performance status (PS) and prior immunotherapy (IT). 120 pts were required for 1:1 randomization to have ≥ 80% power to detect a hazard ratio (HR) of 0.6 (corresponding to a median OS of 10 mo in arm A and 6 mo in arm B) using a 1-sided log-rank test P=0.10). Key secondary endpoints included progression-free survival (PFS), adverse events (AEs), and p16 status. Results: Pts (n=125) were randomized (arm A, 65; arm B, 60). PS and prior IT were balanced between the arms. Median (95% CI) follow-up for OS was 15.9 (15.0–19.4) mo. Median OS was 9.7 (7.3–13.9) mo in arm A and 7.8 (6.7–10.6) mo in Arm B (stratified by PS: HR=0.82 [95% CI, 0.54–1.25], P=0.18). Median PFS was 3.9 mo in arm A and 4.6 mo in arm B (stratified by PS: HR=1.00 [0.7–1.5], P=0.5). Hematologic AEs were more common in arm A. Only 11 pts (9%) received IT after being treated on the trial. Conclusions: Among pts with platinum-resistant, HPV-unrelated HNSCC, PAL plus cetuximab resulted in a trend of prolongation of median OS compared with cetuximab. Clinical trial information: NCT02499120.

Randomized phase II trial of single agent erlotinib vs. standard chemotherapy in patients with advanced non-small cell lung cancer (NSCLC) and performance status (PS) of 2

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7022-7022 ◽  
Author(s):  
R. Lilenbaum ◽  
R. Axerold ◽  
S. Thomas ◽  
A. Dowlati ◽  
L. Seigel ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Randomized Phase Ii ◽  
Never Smokers ◽  
And Performance

7022 Background: A previous CALGB trial suggested a benefit for carboplatin-paclitaxel (CP) over P alone in pts with PS 2. Erlotinib (E) has activity in previously treated pts with low PS but has not been formally tested in 1st line. Methods: In a multi-center randomized phase II trial, untreated pts with advanced NSCLC and PS 2 were randomized to E 150 mg daily or CP (AUC 6 and 200 mg/m2) for 4 cycles. Pts in CP who progressed, did not tolerate, or refused further therapy were allowed to cross over to E. The primary endpoint was progression-free survival (PFS). QoL analysis was performed in all pts and tumor samples were obtained whenever possible. Results: As of 12/05, 98 of 102 projected pts have been accrued. Results are reported for 88 (46 E; 42 CP). Demographics were balanced except for more females in E (59%) than CP (45%). Most pts had stage IV adenoca histology. Never-smokers comprised 13% and 7% of pts respectively. Response for E: 2% PR and 30% SD; for CP, 10% PR and 45% SD. Gr 2–4 toxicities for E: rash (34%) and diarrhea (11%); for CP: nausea (12%), neuropathy (14%) and fatigue (29%). Median PFS was 2.5 mo for E (95%CI 1.28 - 2.79) and 4.0 mo for CP (95%CI 2.66 - 4.86). Of 42 pts in CP, 21 have crossed over to E. Conclusions: This is the first randomized phase II trial of E in PS 2 patients. Based on preliminary results, PS 2 patients seemed to fare better with standard CP than single agent E as initial therapy. Mature survival and QoL data will be available in June. [Table: see text]

Concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in advanced non-small cell lung cancer (NSCLC): A randomized phase II selectional trial SWOG 0342

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7015-7015 ◽  
Author(s):  
K. Kelly ◽  
R. S. Herbst ◽  
J. J. Crowley ◽  
J. McCoy ◽  
J. N. Atkins ◽  
...  
Keyword(s):  
Phase Ii ◽  
Randomized Clinical Trials ◽  
Kinase Inhibitors ◽  
Phase Ii Trial ◽  
Performance Status ◽  
Concurrent Chemotherapy ◽  
Phase Iii ◽  
Phase Iii Trial ◽  
Egfr Signaling Pathway ◽  
Randomized Phase Ii

7015 Background: Randomized clinical trials have failed to show a survival benefit for small molecule EGFR tyrosine kinase inhibitors plus chemotherapy in patients with advanced NSCLC. In contrast, pilot trials of EGFR targeted antibodies plus chemotherapy have suggested enhanced anti-tumor activity. This large randomized phase II trial was designed to select a cetuximab -chemotherapy regimen for future evaluation in a phase III setting. Methods: Untreated patients (pts) with stage IIIB (by pleural effusion) or IV (without brain metastases) NSCLC, with a performance status of 0–1 and adequate organ function were randomized to received paclitaxel (P) 225 mg/m2 and carboplatin (Cb) AUC=6 every 3 weeks plus cetuximab (C) 400 mg/m2 loading dose followed by 250 mg/m2, weekly for 4 cycles followed by maintenance C or the same doses of PCb for 4 cycles followed by C. C was continued until disease progression or 1 year of therapy. The primary endpoint was overall survival; the statistical design required a median survival of ≥ 10 months for a regimen to be selected for subsequent phase III trial evaluation. The probability of correctly choosing the superior arm is 91% when the true hazard ratio is 1.3. Results: From July 2004 to June 2005, 225 eligible pts were enrolled into the study. Preliminary results are described below: Conclusions: At the time of this analysis, efficacy and toxicity were similar in the two treatment arms; both regimens were well tolerated. Assuming these results are sustained, the concurrent regimen of PCb + cetuximab has met the criteria for continued evaluation. A phase II trial of PCb + cetuximab + bevacizumab (B) is in development in anticipation of a phase III trial testing PCbB ± cetuximab. Molecular correlative studies of the EGFR signaling pathway are ongoing. [Table: see text] [Table: see text]

Treatment outcome for metastatic papillary and chromophobe renal cell carcinoma (RCC) patients treated with tyrosine-kinase inhibitors (TKIs) sunitinib and sorafenib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5037-5037 ◽  
Author(s):  
A. Plantade ◽  
T. Choueiri ◽  
B. Escudier ◽  
B. Rini ◽  
S. Negrier ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Clear Cell ◽  
Progression Free Survival ◽  
Categorical Variables ◽  
Clinical Activity ◽  
Exact Test ◽  
Entire Cohort ◽  
Number Of Patients ◽  
Clear Cell Rcc ◽  
Tki Treatment

5037 Background: Sunitinib (SUNI) and sorafenib (SORAF) are novel TKIs that have shown significant clinical activity in metastatic clear-cell RCC. Papillary (PAP) and chromophobe (CHRM) histologies represent the majority non-clear-cell RCC. The activity of SUNI and SORAF in non-clear cell histologies has not been evaluated. Methods: Clinical features at study entry and treatment outcomes were evaluated in all patients (pts) with metastatic PAP and CHRM RCC who received either SUNI or SORAF as their initial TKI treatment at one of five different cancer centers in France and USA between 2002 and 2006. Descriptive statistics were used to evaluate the collected data. Overall Response rate (ORR) was investigator-assessed per RECIST criteria. Fisher’s exact test was used for categorical variables and the Kaplan-Meier method was used to estimate survival (Overall Survival (OS) and progression-free survival (PFS)). Results: Median age for the 53 patients was 59 years and 64% were male. The number of patients with PAP and CHRM histologies were 41 (77%) and 12 (23%), respectively. Nephrectomy was performed in 87% of patients and 33/53 (62%) of pts were previously treated (26/33, 79%, with cytokines). ORR, PFS and OS for the entire cohort were 10%, 8.9 months (m) and 12.2 m, respectively. Twenty (38%) and 33 (62%) pts were treated with SUNI and SORAF, respectively. 3/12 (25%) of CHRM pts had an ORR vs. 2/41(4.8%) with PAP histology (P=0.07). PFS for CHRM pts was 9.3 m compared to 6.6 m for PAP pts (p=0.07). OS was not different across histologies and type of TKI received. SUNI treated pts had an ORR of 15% and PFS of 11.9 m compared to 6% (p=0.3) and 5.5 m for SORAF pts (p=0.002), respectively. Other factors found to be associated with shorter PFS include ECOG PS >0 (p=0.03) and hemoglobin< normal (p=0.02). Conclusions: TKI may have activity in metastatic CHRM RCC, similar to what is seen in clear-cell histology. Minimal activity however is noted in PAP RCC, justifying continued investigations of novel agents in this histology. No significant financial relationships to disclose.

Phase II randomized trial of docetaxel plus cetuximab or bortezomib in patients with advanced NSCLC and performance status (PS) 2—CALGB 30402

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7595-7595 ◽  
Author(s):  
R. Lilenbaum ◽  
X. Wang ◽  
L. Gu ◽  
J. Kirshner ◽  
E. Vokes
Keyword(s):  
Phase Ii ◽  
Type I Error ◽  
Advanced Nsclc ◽  
Performance Status ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Hematologic Toxicity ◽  
Type I ◽  
Weekly Schedule ◽  
Male Response

7595 Background: There is no standard treatment for patients (pts) with advanced NSCLC and PS 2. Docetaxel (D) is active and well tolerated on a weekly schedule. Cetuximab (C) and Bortezomib (B) are new agents with activity in NSCLC. We explored these two new combinations in PS 2 pts. Methods: In a multi-center randomized phase II trial, untreated pts with advanced NSCLC and PS 2 were randomized to D 30 mg/m2 d1,8,15 q. 28 days in combination with either C 400 mg/m2 week 1 then 250 mg/m2 weekly, or B 1.6 mg/m2 d1,8,15 q. 28 days for 4 cycles. Pts with CR/PR/SD were allowed to continue C or B until PD. The study was non-comparative and the primary endpoint was progression-free survival (PFS) rate at 6 months. The trial had a type I error of 0.0746 and power of 0.9 to differentiate a 6-mo PFS of <20% vs. >42%. Results: 64 pts were enrolled between 7/05 and 9/06. 5 were ineligible and 3 never received protocol treatment. Results are reported for 55 pts (27 D+C; 28 D+B). Most pts had stage IV adenoCa and 13% had brain metastases. Median age was 70 (range, 35–88) and 65% were male. Response: 10.5% for D+C and 13.6% for D+B. Median PFS was 3.1 mo for D+C and 1.8 mo for D+B. PFS rates at 4 mo (data not yet mature for 6-mo): 33% and 28%, respectively. Median survival: 3.8 mo for D+C and 3.3 mo for D+B. Gr 3/4 hematologic toxicity was 17% in both arms. Gr 3/4 non-heme toxicities were 44% in D+C and 36% in D+B arm. 5 pts died of treatment-related toxicities (3 D+C; 2 D+B). Conclusions: These results confirm the poor prognosis associated with a PS of 2. Based on our preliminary analysis, neither combination produced results that justify further research in this subset of patients. The treatment of PS 2 patients with advanced NSCLC remains a vexing problem and new approaches are urgently needed. No significant financial relationships to disclose.

Phase I randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib as first-line treatment in patients with metastatic pancreatic cancer (SWOG-0727).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 198-198 ◽  
Author(s):  
Philip Agop Philip ◽  
Bryan H. Goldman ◽  
Ramesh K. Ramanathan ◽  
Heinz-Josef Lenz ◽  
Andrew M. Lowy ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase I ◽  
Phase Ii ◽  
Complex Disease ◽  
Performance Status ◽  
Fasting Blood Glucose ◽  
Progression Free Survival ◽  
Sensitivity Analyses ◽  
Randomized Phase Ii ◽  
Grade 3

198 Background: Targeting a single pathway in pancreatic adenocarcinoma (PAC) did not impact the natural history of this molecularly complex disease. Epidermal growth factor receptor (EGFR) targeting with erlotinib marginally improved the outcome of patients with advanced disease. We tested the hypothesis that if the EGFR and IGF-1R pathways are simultaneously blocked then progression free survival (PFS) would be significantly improved by abrogating reciprocal signaling. Methods: S0727 was a phase I/randomized phase II (RP2) study testing the anti-IGF-1R monoclonal antibody cixutumumab combined with erlotinib and gemcitabine in patients with metastatic PAC. The control arm was erlotinib plus gemcitabine. The primary endpoint of the RP2 portion of the study was PFS. Eligibility included patients with untreated metastatic disease, performance status 0/1, fasting blood glucose less than institutional upper limit of normal, and willingness to provide tissue and blood specimens for correlative studies. Results: In Phase I portion (n=10) safety of cixutumumab 6 mg/kg IV/wk, erlotinib 100 mg/day orally and gemcitabine 1000 mg/m2 IV D 1,8, and 15 of a 28-day cycle was established. In the RP2 portion (n=124) 114 eligible patients (median age 63) were included. On the cixutumumab arm, 59% of patients were female vs. 41% on control arm. Median PFS and overall survival were 4 and 7 months, respectively, in both arms. Four patients on cixutumumab remain on treatment; sensitivity analyses show no impact on the conclusions. Major grade 3 and 4 toxicities were (cixutumumab/control) elevation of transaminases (12%/6%), fatigue (24%/21%), gastrointestinal (35%/28%), and hematologic (53%/39%). Grade 3/4 hyperglycemia was seen in 27% of patients on cixutumumab. Grade 3 or 4 kin toxicity was similar in both arms of the study (< 5%). Five treatment-related deaths were reported: 2 cardiac on each arm, 1 pulmonary on cixutumumab. Conclusions: IGF-1R inhibitor cixutumumab did not improve the progression free or overall survival in patients with metastatic PAC treated with erlotinib and gemcitabine in a molecularly unselected population.

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