Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC): Planned interim efficacy and safety analysis.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 305-305
Author(s):  
Sukeshi Patel Arora ◽  
Jennifer L. Moseley ◽  
Laura LaNiel Tenner ◽  
Luisa Arellano ◽  
Mary Salazar ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Hepatocellular Cancer ◽  
Safety Analysis ◽  
Efficacy And Safety ◽  
First Line ◽  
Clinical Safety ◽  
Advanced Hcc

305 Background: SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report planned interim analysis for our first-line cohort. Methods: Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, response by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Planned interim efficacy and safety analysis approved by DSMB is reported here. Results: For cohort 1, n = 19. Median age 63.5 (51-80). 80% Male; 65% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 32%. Etiology of cirrhosis: HCV 84%, ETOH 26%, NASH 5%. BCLC B 21%, C 70%. AFP > 400: 47%, PVT: 32%, metastases: 64%, post-transplant: 21%. Reason off study: PD (n = 10), toxicity (n = 2), lost to f/u (n = 1), withdrew (n = 1). N = 16 completed C1, n = 2 remain on study. mTTP is 4.2 months (95% CI: 3.7-NA). mOS 13.8 months (95% CI: 13.8-NA). Response Rate (CR+PR): 25%. Best response: CR n = 1 (6%), PR n = 3 (19%), SD n = 7 (44%). 4+ cycles: n = 9 (56%). % alive. Median duration of response 7.6 months (3.67-20). Gr 1/2 AEs as expected from SOR. Gr 3: AST elevated (n = 1), diarrhea (n = 1) due to SOR. Gr 2 rash (n = 1) due to HCQ. No Gr 4/5. Dose reduction: 70% for SOR, 0% for HCQ. PD analysis on the 3 responders show favorable immune profile changes (increase in cytotoxic T cells and decrease T Regs). Conclusions: SOR/HCQ had a better response rate (25%) than historically SOR alone (2%) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may have a role in patients with CP B cirrhosis, transplant or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing. Clinical trial information: NCT03037437.

A phase II study of irinotecan, oxaliplatin, 5-fluorouracil, leucovorin (FOLFOXIRI) as a first-line chemotherapy in metastatic gastric cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4076-4076
Author(s):  
J. Lee ◽  
W. Kang ◽  
S. Lee ◽  
J. Kwon ◽  
H. Kim ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase Ii ◽  
Combination Chemotherapy ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Metastatic Gastric Cancer ◽  
Efficacy And Safety ◽  
First Line ◽  
Grade 3

4076 Background: Previous phase II study showed a high efficacy and safety of FOLFOXIRI (irinotecan, oxaliplatin, 5-fluorouracil, leucovorin) combination chemotherapy in metastatic colorectal cancer. This non-randomized open label phase II study evaluated the efficacy and safety of FOLFOXIRI in metastatic or recurrent gastric cancer patients. Methods: Patients with: histologically proven, bidimensionally measurable, metastatic gastric adenocarcinoma, age 18 - 70 years, with a performance status 0 - 2, no prior chemotherapy or at least 12 months after adjuvant therapy, life expectancy > 3 months, signed written informed consent were eligible. Treatment consisted of irinotecan 150 mg/m2 day 1, oxaliplatin 85 mg/m2 day 1, leucovorin 100 mg/m2 day and 5-fluorouracil 2000 mg/m2 as a 48-h continuous infusion starting on day 1, repeated every 2 weeks until unacceptable toxicity, patients’ refusal, or up to 12 cycles. The planned sample size was 48 and the primary endpoint was response rate. Results: From August 2004 to August 2005, 48 patients were prospectively enrolled. The median age was 54 years (24 - 69) and male:female ratio was 1.3:1. In total, 379 cycles were administered with a median of 9 cycles per patient (range, 1–12) and 45/48 patients were evaluable for treatment response. Three patients were not assessable for response due patients’ refusal for further chemotherapy following the first cycle. By per-protocol analysis, the objective response rate was 73.3 % (95% CI, 60.8–85.8) with 2 CRs and 31 PRs. Four patients (9%) had stable disease and 8 patients (18%) had progressive disease. The estimated median survival of all patients was 14.0 months (95% CI, 11.8 - 16.2 ) and the estimated median time-to-progression was 8.9 months (95% CI, 6.7–11.0). In total of 379 cycles administered, most common grade 3/4 toxicities were neutropenia (11% of all cycles) and emesis (12%). Grade 2 peripheral neuropathy occurred in 5 patients. One (2%) patient had severe tumor bleeding and 5 (10%) patients experienced grade 3 diarrhea. Conclusions: FOLFOXIRI combination chemotherapy showed a very promising preliminary anti-tumor activity and was generally well tolerated as a first-line treatment for patients with metastatic gastric cancer. No significant financial relationships to disclose.

Phase II study of binimetinib with imatinib in patients with unresectable KIT-mutant melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9594-TPS9594
Author(s):  
Katy K. Tsai ◽  
Iwei Yeh ◽  
Adil Daud ◽  
Ari Oglesby
Keyword(s):  
Phase Ii ◽  
Null Hypothesis ◽  
Response Rate ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Specific Treatment ◽  
Type I ◽  
True Response ◽  
Phase Ii Studies

TPS9594 Background: Immune checkpoint inhibitors (ICI) have transformed treatment for patients (pts) with advanced melanoma, as have BRAF/MEK inhibitors for pts with BRAF V600-mutant melanoma. However, pts with acral or mucosal melanomas are in particular need of more options given a lower objective response rate (ORR) to ICI, and lower incidence of BRAF V600 driver mutation. Such BRAF mutations are found in only 5-10% of acral/mucosal melanomas, while KIT mutations/amplifications are found in 10-20%. Even when present, a KIT alteration does not guarantee response to KIT inhibition, with only about one-third responding as previously shown in 3 phase II studies. A significant number of KIT-mutant melanomas have been shown to demonstrate NF1 or SPRED1 loss, with recent preclinical work showing that such alterations are associated with the loss of negative suppression of RAS, resulting in RAS activation and MEK dependence. We hypothesize that NF1 or SPRED1 loss cooperates with KIT mutations to drive melanomagenesis and resistance to KIT inhibition, and propose to target this vulnerability with a combination approach to targeted therapy. This phase II study will be the first to evaluate the efficacy and safety of binimetinib plus imatinib in pts with KIT-mutant melanoma. Methods: This is an investigator-initiated phase II study of binimetinib in combination with imatinib in pts with BRAF V600 WT, KIT-mutant unresectable melanoma who have progressed on or who are ineligible for ICI (NCT04598009). Pts will be ≥18 yo with performance status ECOG 0-2, and have unresectable Stage IIIB/C/D or Stage IV melanoma that is BRAF V600 WT and KIT-mutant by CLIA-certified testing platform. Pts will have progressed on prior ICI or other standard-of-care (SOC) therapies, or be ineligible for or unable to tolerate SOC therapies. Pts with brain metastasis will be eligible if clinically stable and determination made that no CNS-specific treatment is required prior to study start. Pts previously treated with a MEK inhibitor will be excluded. A Simon 2-stage Minimax design will be used; the null hypothesis that the true response rate is 0.1 will be tested against a one-sided alternative. 15 pts will be accrued in the first stage. If there are £1 responses, the study will be stopped. Otherwise, 10 additional pts will be accrued for a total of 25. The null hypothesis that the true response rate is 0.1 will be rejected if ≥6 responses are observed. This yields a type I error rate of 0.05 and power of 0.8017 when the true response rate is 0.3.Primary endpoint: ORR (RECIST). Secondary endpoints: duration of response, progression-free survival, overall survival, clinical benefit rate (CR, PR, or SD ≥16 weeks), safety profile (CTCAE). Exploratory objectives to include investigations of association between clinical response and baseline NF1 and SPRED1 status, and of pathologic correlates of acquired resistance. Study began enrolling pts in December 2020 and is ongoing. Clinical trial information: NCT04598009.

Safety and efficacy of nivolumab plus recombinant human endostatin in previously treated advanced non-small cell lung cancer: A prospective and multicenter phase 2 trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21079-e21079
Author(s):  
Weize Lv ◽  
Beilong Zhong ◽  
Wenhua Zhao ◽  
Zhong Lin ◽  
Xiaofeng Pei ◽  
...  
Keyword(s):  
Adverse Events ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Efficacy And Safety ◽  
Small Cell Lung ◽  
First Line ◽  
Recombinant Human Endostatin ◽  
Phase 2 Trial

e21079 Background: Although the administration of immune checkpoint inhibitors (ICIs) and antiangiogenic agents in advanced non–small-cell lung cancer (NSCLC) has been well established, evidence supporting the combination of immune checkpoint inhibitors plus antiangiogenic drugs in previous treatment patients with advanced NSCLC is insufficient. We aimed to investigate the efficacy and safety of nivolumab combined with recombinant human endostatin (rh-Endostatin) as second-line or later treatment for advanced NSCLC. Methods: In this prospective and multicentre phase 2 trial we enrolled patients with advanced NSCLC who had not responded to standardized first-line treatment regimen from two cancer centres in China. Eligible patients were those aged 18-75 years without ICIs in first-line treatment who received nivolumab (3mg/kg, intravenous drip, day 1) every 2 weeks and rh-Endostatin (30 mg, 24-hour continous intravenous infusion，day 1–7) every 4 weeks till disease progression or discontinuation. The primary end points were objective response rate and safety. This study is registered with Chinese Clinical Trial Registry, number ChiCTR1900023664. Results: A total of 35 patients (median age, 60 years; range, 37-72 years) received nivolumab and rh-Endostatin. Median previous treated line of eligible patients was 2 lines (range, 1-7 lines). Patients received a median of 2 cycles of therapy (range, 1-14 cycles). Eleven of 33 evaluable patients achieved confirmed partial response with an objective response rate of 33.3% (11/33, 95% confidence interval [CI]: 17.2% – 49.4%) and disease control rate of 60.6% (20/33,95%CI:43.9%–77.3%). Median follow-up was 8.2 months (range: 0.9 –17.1). Median progression-free survival was 7.1 months (95% CI: 1.2m–13.0m), median overall survival was not reached and the 6-month overall survival rate was 54.5% (95% CI:37.6%–71.4%). The predominant grade 1-2 adverse events were thyroiditis, arrhythmia, hypertension. The grade 3 treatment-related adverse events were pneumonitis (3/35, 8.6%), hypertension (1/35, 2.9%) and atrial fibrillation (1/35, 2.9%), respectively. No grade 4 or 5 treatment-related adverse events were observed. Conclusions: To the best of our knowledge, this is the first prospective study that assessed nivolumab combined with rh-Endostatin as second-line or later treatment in pretreated patients with advanced NSCLC. In view of its encouraging efficacy and safety profile, nivolumab plus rh-Endostatin represents a promising treatment regimen in this patient population. Clinical trial information: ChiCTR1900023664.

Procarbazine and High-Dose Tamoxifen as a Second-Line Regimen in Recurrent High-Grade Gliomas: A Phase II Study

1999 ◽  
Vol 17 (2) ◽  
pp. 645-645 ◽  
Author(s):  
Alba A. Brandes ◽  
Mario Ermani ◽  
Sergio Turazzi ◽  
Elvira Scelzi ◽  
Franco Berti ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Chemotherapy Regimen ◽  
Phase Ii Study ◽  
Tumor Control ◽  
High Dose ◽  
High Grade ◽  
Second Line ◽  
First Line ◽  
High Grade Gliomas

PURPOSE: A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen. Our aim was to investigate the efficacy of procarbazine (PCB) combined with high-dose tamoxifen in relation to tumor control, toxicity, and time to progression (TTP). PATIENTS AND METHODS: Fifty-three patients were treated with procarbazine in repeated 30-day courses at 100 mg/m2/d plus tamoxifen 100 mg/d, with a 30-day interval between courses. Thirty-four patients had been pretreated with a first-line nitrosourea-based chemotherapy regimen (group A), and 19 patients had also been pretreated with a second-line chemotherapy regimen consisting of carboplatin and teniposide (group B). Twenty-one of the patients had also been procarbazine pretreated, whereas the remaining 32 patients were not procarbazine pretreated. RESULTS: The response was assessed in 51 patients, 28 of whom had glioblastoma multiforme (GBM) and 23 of whom had anaplastic astrocytoma (AA). There were two complete responses (CR) (4%) and 13 partial responses (PR) (25.5%). The overall response rate (CR + PR) was 29.5% (SE, 6.4; 95% confidence interval [CI], 23 to 35.8). Seventeen patients (32%) had stable disease (SE, 6.2; 95% CI, 21 to 33.6). The median TTP was 13 weeks for patients with GBM and 33 weeks for patients with AA (P = .006). The median survival time (MST) was 27 weeks for patients with GBM and 57 weeks for those with AA (P = .006). CONCLUSION: Combined PCB and tamoxifen as a second-line regimen gave a reasonably high response rate in patients with heavily pretreated high-grade gliomas. However, although it resulted in an improvement in the patients' quality of life and/or performance status, it was not followed by an increased TTP or MST.

Multi-institutional phase II study of carboplatin-gemcitabine combination chemotherapy in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18179-18179
Author(s):  
J. Sasaki ◽  
H. Uramoto ◽  
K. Kashiwabara ◽  
H. Kishi ◽  
E. Moriyam ◽  
...  
Keyword(s):  
Phase Ii ◽  
Combination Chemotherapy ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Group Performance ◽  
Phase Ii Study ◽  
Single Agent ◽  
Objective Response ◽  
Efficacy And Safety ◽  
Grade 3

18179 Background: Because elderly pts may tolerate platinum-based combination chemotherapy poorly, single-agent chemotherapy is selected for the treatment regimen. However, retrospective subgroup analyses have consistently indicated that elderly pts indeed benefit from platinum-based combination chemotherapy as well as their younger counterparts. This phase II study evaluated the efficacy and safety of carboplatin-gemcitabine combination chemotherapy in elderly pts with advanced NSCLC. Methods: Fifty-four pts aged more than 70 years old (median, 77; range, 70–88) with previously untreated advanced NSCLC were enrolled on this trial. Additional criteria included the presence of measurable lesions, an Eastern Cooperative Oncology Group performance status of 0 or 1, and adequate organ function. Pts received carboplatin at an area under the curve of 4 mg/ml/min on the first day and gemcitabine at 1000 mg/m2 on the first and eighth day of consecutive 3 week periods. The primary endpoint was to determine the objective response rate of this platinum-doublet regimen. The RECIST criteria were used to measure response. Results: Enrolled pts included 15/39 with stage IIIB/IV diseases. Fifty-one out of enrolled pts were eligible for efficacy and safety analyses. The median number of treatment cycles was 4 (range, 1–7). Fifteen partial responses (response rate: 29%) were obtained. The median TTP was 118 days. Hematological toxicities of grade 3/4 included leukopenia (46%), neutropenia (72%) and thrombocytopenia (50%). Non-hematological toxicities of grade 3/4 included nausea (6%), appetite loss (7%), fatigue (7%) and infection (9%). Conclusions: The combination carboplatin-gemcitabine at these doses has shown activity with a favorable toxicity profile for fit elderly pts with advanced NSCLC. No significant financial relationships to disclose.

Phase II study of ifosfamide, carboplatin and etoposide (ICE) in recurrent glioblastoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2066-2066
Author(s):  
T. Aoki ◽  
K. Nojima ◽  
T. Mizutani ◽  
M. Ishikawa ◽  
A. Takasu ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Recurrent Glioblastoma ◽  
First Line ◽  
Open Label ◽  
Free Survival ◽  
Secondary Endpoints

2066 Background: To evaluate the efficacy and tolerability of ifosfamide, carboplatin and etoposide ( ICE ) in patients with recurrent glioblastoma. Methods: This was an open-label, single-center phase II trial. Forty-two patients with first recurrent glioblastoma after surgery, standard radiotherapy and a first-line temozolomide-based or ACNU-based chemotherapy, were enrolled.The primary endpoint was progression-free survival at 6 months ( PFS-6 ), and secondary endpoints were response rate, toxicity, and survival. Chemotherapy consisted of Ifosfamide ( 700 mg / m2 on day 1, 2 and 3 ), carbopaltin ( 100 mg / m2 on day 1 ), etoposide ( 70 mg / m2 on day 1, 2, and 3 ), every 6 weeks. Results: PFS-6 was 37 %. The median PFS was 17 weeks. Response rate was 27 %. Adverse events were generally mild ( grade 1 or 2 ) and consisted mainly of alopecia. Conclusions: This regimen is well tolerated and has activity in patients with recurrent glioblastoma. No significant financial relationships to disclose.

CETUFTIRI, a new combination of UFT with leucovorin (LV), irinotecan, and cetuximab as first-line treatment for patients (pts) with unresectable metastatic colorectal cancer (mCRC): Preliminary results from a multicenter phase II trial

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4087-4087 ◽  
Author(s):  
J. Bennouna ◽  
R. Faroux ◽  
E. François ◽  
C. Ligeza ◽  
C. El Hannani ◽  
...  
Keyword(s):  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
New Combination ◽  
Line Treatment ◽  
First Line ◽  
Egfr Expression ◽  
First Line Treatment

4087 Background: A phase II study (ASCO 2004) established that the combination of UFT (tegafur-uracil) with LV and irinotecan (TEGAFIRI) could be safely administered to pts with unresectable mCRC, with an objective response rate (ORR) of 34% and a median time to progression (TTP) of 5.7 months. We initiated CETUFTIRI, a phase II study, to evaluate the efficacy and tolerability of cetuximab added to TEGAFIRI in chemonaïve pts with unresectable mCRC. Methods: Patients in this single-stage study were aged =18 years, with histologically or cytologically confirmed, bidimensionally measurable mCRC, ECOG performance status 0 or 1, and adequate bone marrow, renal, and hepatic function. EGFR expression was not an inclusion criterion. Treatment consisted of UFT 250 mg/m2/day d1–14, LV 90 mg/day d1–14, and irinotecan 250 mg/m2 d1 every 3 weeks, plus cetuximab 400 mg/m2 week 1 then 250 mg/m2 weekly thereafter. The primary endpoint was ORR and the planned sample size was 61 pts. The study is now closed to accrual. Results: To date, 48 patients are evaluable for safety and 31 are evaluable for efficacy. Patient characteristics (n=48): median age 65 years (range 45–84 years); ECOG PS 0/1: 73/27%; male 65%; tumor sites: colon 69%; rectum 17%; junction 14%; liver metastasis 83%; lung metastasis 46%; other 27%. Adverse events per patient (n=48) after a total of 230 cycles were: grade G3 mucositis 10%; G3/4 neutropenia 10%; G3 nausea/vomiting 8%; G3 asthenia 6%; febrile neutropenia 6%; G3 hypokalemia 6%; G3/4 anemia 4%; G3 diarrhea 2%; acne-like rash G1/2 50% (G3 4%); infusion- related reaction to cetuximab 6%. Two of 31 evaluable pts had a complete response and 11 had a partial response, for an ORR of 42%; 5 pts had stable disease (16%) and 11 pts had progressive disease (35.5%). An independent radiologist review is planned for all 61 pts included up to December 2006. Conclusions: The CETUFTIRI combination seems to have an acceptable toxicity profile with an attractive objective response rate in the first-line treatment of pts with mCRC. No significant financial relationships to disclose.

Efficacy and safety of approved first-line tyrosine kinase inhibitor (TKI) treatment in patients with metastatic renal cell carcinoma (mRCC): A network meta-analysis based on phase II/III randomised clinical trials (RCTs).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16074-e16074
Author(s):  
Kirsi Manz ◽  
Klaus Fenchel ◽  
Andreas Eilers ◽  
Jon Morgan ◽  
Kirsten Wittling ◽  
...  
Keyword(s):  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Cochrane Central Register ◽  
Line Treatment ◽  
Efficacy And Safety ◽  
First Line ◽  
Manual Search ◽  
Grade 3 ◽  
First Line Treatment

e16074 Background: During the last decade several novel treatment options including TKIs and immune checkpoint inhibitors have been developed for the treatment of mRCC patients. However, results from direct comparisons (head-to-head RCTs) to determine the optimal treatment are lacking for most of these agents. In this network meta-analysis we attempted to indirectly compare efficacy and safety of first-line TKIs in patients with mRCC. Methods: PubMed, Embase, Medline, the Cochrane Central Register of Controlled Trials were searched (English language only). Abstracts of conferences of relevant medical societies were also included from database inception (January 1, 2007) to January 15, 2019. A systematic manual search (including data requests from the publication authors) was also performed. For the purpose of this network meta-analysis only phase II/III RCTs assessing approved first-line TKI therapy for mRCC were analysed. The analysis was done using the software R with the netmeta package. Progression-free survival (PFS) was the primary endpoint; grade 3 and 4 adverse events (AEs) were secondary endpoints. Results: A database search identified 12 studies meeting the eligibility criteria reporting on 4,460 patients. For PFS cabozantinib and sunitinib were found to be superior to sorafenib, however, when compared to tivozanib, PFS did not significantly differ between the TKIs. Furthermore, tivozanib was found to have the highest probability of being the safest drug as first-line treatment in terms of grade 3 and 4 AEs (ranking safety, p score 0.9344). Conclusions: No significant PFS differences for all TKIs currently used for first-line treatment of mRCC have been found when compared with tivozanib. Compared with all approved TKIs tivozanib appears to be the best choice for first-line treatment of these patients because it has demonstrated the most favourable safety profile. These results may provide guidance to oncologists when making treatment decisions for mRCC patients.

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