A Phase II study of axitinib (AG-013736), a potent inhibitor of VEGFRs, in patients with advanced thyroid cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 5529-5529 ◽  
Author(s):  
S. Kim ◽  
L. S. Rosen ◽  
E. E. Cohen ◽  
R. B. Cohen ◽  
A. Forastiere ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Cell Cancer ◽  
Safety Data ◽  
Thyroid Tumor ◽  
Ecog Performance Status ◽  
Advanced Thyroid Cancer

5529 Background: Elevated levels of VEGF have been found in thyroid tumor tissue compared to normal thyroid. Axitinib (AG-013736) is a novel small molecule inhibitor of the receptor tyrosine kinases with picomolar potency against VEGFR 1, 2 & 3 and nanomolar potency against PDGFR-beta and KIT. A phase I study in solid tumors identified 5 mg BID as the therapeutic dose. A phase II study in renal cell cancer demonstrated significant efficacy with a response rate (RR) of 46% (Rini et al, ASCO 2005). This study examined the safety and efficacy of AG-013736 (AG) therapy for advanced thyroid cancer. Methods: 32 patients (pts) refractory to or not suitable candidates for Iodine (131I) treatment were treated with AG 5 mg p.o. BID. Eligibility included measurable disease and ECOG performance status (PS) of 0 or 1. A Simon 2 stage minimax design was used (alpha = 0.1; beta = 0.1; null response rate (RR) = 5%; alternative RR = 20%). Results: The median age of 32 enrolled pts was 63 yrs (35–81), 20 (63%) were male, 12 (38%) were female. Histological subtypes include papillary: 19 pts (59%); follicular- 9 pts (28%), medullary- 2 pts (6%) and anaplastic-2 pts (6%). 25 pts (78%) had prior surgery, 19 pts (59%) had prior 131I treatment, 15 pts (47%) had prior RT, 6 pts (19%) had prior Adriamycin. Best response as assessed by RECIST criteria is PR in 3 pts with 38%-48% regression and additional unconfirmed PRs in 3 pts. Two pts (follicular) have PR>12 mos. Response assessments are ongoing. 12 patients have discontinued treatment: 6 pts (19%)-progression, 3 pts-adverse events (AEs) and 3 pts-other. Twenty pts (63%) remain on study. The range for time on study is (6, 469) days. Median progression free survival has not been reached. Preliminary safety data for 17 pts indicate most common treatment emergent AEs as fatigue (9 pts), nausea (5 pts), proteinuria ( 5pts ), dizziness (4pts). Gr. 3 AEs include proteinuria ( 2pts ), cough (1pt), dyspnea (1 pt), abdominal pain (1pt), dysphagia (1pt), fatigue (1pt), muscle weakness (1pt), anorexia (1pt). Gr. 2 hypertension was observed in 2 pts. Conclusions: AG-013736 has substantial anti-tumor activity in advanced thyroid cancer. Therapy is well tolerated with manageable toxicity. Further investigation in this setting is warranted. [Table: see text]

Randomized phase II study of sorafenib with or without everolimus in patients with radioactive iodine refractory Hürthle cell thyroid cancer (HCC) (Alliance A091302/ ITOG 1706).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6076-6076
Author(s):  
Eric Jeffrey Sherman ◽  
Nathan R. Foster ◽  
Yungpo Bernard Su ◽  
Ardaman Shergill ◽  
Alan Loh Ho ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase Ii ◽  
Radioactive Iodine ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Progression Free Survival ◽  
Rank Test ◽  
Ecog Performance Status ◽  
Significance Level

6076 Background: HCC is a rare subtype of follicular cell thyroid cancer that has been poorly studied in the past. Recent genomic studies have shown the PI3K/Akt/mTOR pathway is frequently altered in HCC. In addition, a phase II study of sorafenib (S) and everolimus (E) showed promising data in HCC. A study to evaluate this was initiated through Alliance and the International Thyroid Oncology Group. Methods: Patients (pts) were randomized to either sorafenib and everolimus (SE) vs. sorafenib alone (S). Inclusion criteria included; (1) diagnosis of HCC (confirmed through central review), no prior S or E, refractory to radioactive iodine, progressive disease by RECIST over prior 14 months. Primary endpoint was a comparison of progression-free survival (PFS) between SE and S using a stratified 1-sided log-rank test with 0.20 significance level and a power of 80%. 28 events were needed at final analysis. Secondary endpoints consisted of overall survival (OS), confirmed response rate (RR), and adverse events. Results: 35 pts were randomized from 10/2014 to 9/2019, 34 of which were evaluable for analysis (17-SE; 17-S) because 1 patient cancelled prior to receiving treatment. Median age was 66.5 years and 74% were male. ECOG performance status (PS) was 0 (47%) and PS 1 (53%). 41% had prior systemic treatment for HCC. No significant differences in baseline characteristics were observed between treatment arms. Median follow-up in 22 alive patients was 39.2 months (range: 15.1-64.9). Seven (21%) patients remain on treatment. PFS was significantly improved in the SE arm as compared to the S arm (HR=0.65 (95% CI: 0.26, 1.57); median PFS: SE=24.7 months (95% CI: 6.1-no upper), S=10.9 months (95% CI: 5.5-no upper); stratified 1-sided p=0.1662). OS was similar between the arms (2-sided p=0.4138). Confirmed response rate was similar between arms as well (SE: 18% (3 partial response (PR) vs. S: 24% (3 PR, 1 complete response)); Fisher’s exact p=1.00). Grade 3 adverse event (AE) rates (regardless of attribution) were similar between arms (SE: 77% vs. S: 77%; p=1.00). Each arm had 1 patient with at least one grade 4 AE (SE patient: cardiac arrest, tracheal obstruction, encephalopathy; S patient: mucositis oral) and no grade 5 AEs. Conclusions: PFS was improved with the addition of E to S in this small randomized multi-institutional phase II study done. Accrual was difficult, but these promising results suggest that this combination should be further studied. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Novartis/GSK; ClinicalTrials.gov Identifier: NCT02143726. Clinical trial information: NCT02143726.

Phase II study of irinotecan and paclitaxel for patients with recurrent small cell lung cancer (SCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18011-18011
Author(s):  
T. K. Owonikoko ◽  
S. Ramalingam ◽  
J. Forster ◽  
Y. Shuai ◽  
T. Evans ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Treatment Options ◽  
Objective Response ◽  
Ecog Performance Status ◽  
Stage Design ◽  
Prior Chemotherapy Regimen ◽  
Version 2.0

18011 Background: Recurrent SCLC has a poor prognosis and is devoid of treatment options that improve overall survival. Irinotecan and paclitaxel are both active agents against SCLC, and have synergistic preclinical interactions. We conducted a phase II study to evaluate the efficacy and safety of the combination of irinotecan and paclitaxel for patients with recurrent SCLC. Methods: Patients with SCLC who relapsed following one prior chemotherapy regimen were eligible. Other pertinent inclusion criteria were: ECOG performance status 0–2, adequate bone marrow, hepatic and renal function and willingness to provide informed consent. Patients with untreated brain metastasis were excluded. Paclitaxel (75 mg/m2) and irinotecan (50 mg/m2) were administered on days 1 & 8 of every 3-week cycle. Treatment was continued until progression up to a maximum of 6 cycles or unacceptable toxicity. The primary endpoint was response rate. Toxicity was graded by CTC version 2.0. The simon two-stage design was utilized and the estimated sample size was 55 patients (stage I - 23 patients; stage 2 - 32 patients). The study has a 90% power to detect a response rate of 30%, with an alpha error rate of 10%. Results: 55 patients have been enrolled and complete data are available for 32 patients at the time of this report. Patient baseline characteristics are: male 53%, PS 0–44%; PS 1–47% and PS 2–6%. The median age is 61 years. Fifteen patients received ≥ 4 cycles. Salient grades 3–5 toxicities seen: neutropenia (13%), fatigue (13%); diarrhea (3%), hypersensitivity (3%) and hyponatremia (3%).The objective response rate is 37% (95% CI 19%-55%) with 9 PRs and 1 CR. Additional 8 patients (24%) had stable disease. The median survival is 19.6 weeks (95% CI 15.1–29.4) and the 1-year survival rate is 15%. Conclusions: The combination of irinotecan and paclitaxel is well tolerated and has promising anti-cancer activity in recurrent SCLC. Updated data on all 55 patients will be available at the time of the presentation. No significant financial relationships to disclose.

Docetaxel-carboplatin chemotherapy in combination with cetuximab in patients with locally advanced or metastasized non-small cell lung cancer (NSCLC): Interim results of the nonrandomized phase II study TaxErb

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19062-e19062
Author(s):  
J. R. Fischer ◽  
F. Griesinger ◽  
T. Fink ◽  
E. Buchholz ◽  
T. Salm ◽  
...  
Keyword(s):  
Phase Ii ◽  
Partial Remission ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Locally Advanced ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Ecog Performance Status ◽  
Benefit Risk Assessment

e19062 Background: Combination chemotherapy with carboplatin-docetaxel has been shown to be effective and safe for patients with locally advanced or metastasized NSCLC. The monoclonal anti-EGRF antibody cetuximab has the potential to improve response rates and survival without a substantial increase in toxicity when given in combination with chemotherapy. Methods: Open, non-controlled phase II study with a planned sample size of 70 pts. Pts with locally advanced or metastasized NSCLC, ECOG performance status ≤ 2 and no prior systemic chemotherapy were treated with carboplatin AUC5 (d 1) q4w for 4–6 cycles and docetaxel 35 mg/m2 (d1, 8, 15) q4w; cetuximab 400 / 250 mg/m2 (d 1) q1w until progression or intolerable toxicity (12 month max.). The primary endpoint was response rate defined as complete or partial remission according to RECIST. Secondary endpoints were toxicity, 1 year survival, median and progression free survival. Results: Subject of the interims analysis were 27 pts (25 stage IV, 2 stage IIIb). ECOG 0/1/2 was 33.3%/59.3%/3.7% (1 no data). 63% had prior surgery, 93% prior radiotherapy and all had adjuvant or inductive chemotherapy. Pts received a mean of 3 ± 1.4 cycles docetaxel-carboplatin-cetuximab. 49 adverse events were grade 1–2 and 12 grade 3–5. Skin toxicity (49%; 95%CI: 30%-68%; 41% G1/2, 8% G3/4), dyspnoea (35%; 95%CI: 17%-53%) and diarrhoea (23%; 95%CI: 7 %-39%; 19% G1/2, 4% G3) were most frequent. 11 pts (41%) had toxicity leading to dose reduction. 0 pts had complete and 11 pts had partial remission resulting in a response rate of 40.7% (95%CI: 22%-59%) based on intention to treat. 6 pts had stable disease (22.2%; 95%CI: 7%-38%). 5 pts were not evaluable for response. Conclusions: The combination of carboplatin-docetaxel-cetuximab has an overall acceptable tolerability. With a preliminary response rate of 40.7% the benefit risk assessment was found to be favourable and the study was continued. [Table: see text]

Phase II study of combination therapy with docetaxel, cisplatin, and S-1 (DCS) for advanced gastric cancer: (KDOG 0601)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4555-4555
Author(s):  
N. Nakayama ◽  
W. Koizumi ◽  
T. Sasaki ◽  
S. Tanabe ◽  
K. Nishimura ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
High Response Rate ◽  
Ecog Performance Status ◽  
Eligibility Criteria

4555 Background: Our previous phase I study (Oncology 2008, 75:1–7) provided evidence that combination chemotherapy with docetaxel, cisplatin, and S-1 (DCS) is effective and well tolerated in patients with advanced gastric cancer. The present multicenter phase II study was conducted to confirm the efficacy and toxicity of DCS in advanced gastric cancer. Methods: Eligibility criteria included a histologically proved diagnosis of gastric adenocarcinoma with at least one measurable metastatic lesion, no previous treatment for gastric cancer except for surgery, an ECOG performance status of 0 to 2, and adequate organ function. Docetaxel (40 mg/m2) and cisplatin (70–60 mg/m2) were given intravenously on day 1, and S-1 was given orally at a dose of 40 mg/m2 twice daily from days 1 to day 14 of a 28-day cycle. Patients received a maximum of 6 cycles. Subsequently, patients were given repeated cycles of S-1 plus docetaxel (DS). The primary endpoint was the objective response rate. Results: 59 patients (47 men, 12 women) were enrolled. The median age was 62 (range: 35–75) years. PS 0/1/2 was 40/18/1. The median number of treatment cycles was 7 (DCS 6+DS 1: range, 1–20). Because myeloid suppression and renal dysfunction developed during the study, we lowered the recommended dose of cisplatin from 70 mg/m2 to 60 mg/m2. The dose of cisplatin was 70 mg/m2 in 19 patients and 60 mg/m2 in 40. The overall response rate was 81.3% (48/59; 95% CI, 80.7–91.2). The response rates with cisplatin 70 mg/m2 and 60 mg/m2 were 78.9% (95% CI, 60.5–97.2) and 82.5% (95% CI, 70.7–94.2), respectively. Tumor down-staging was achieved in 9 (18.7%) of the 48 patients who responded to treatment. The median survival time and median progression-free survival were not reached. Grade 3 or 4 major toxicity comprised leukopenia (44.0%), neutropenia (72.8%), anemia (15.2%), febrile neutropenia (13.5%), anorexia (6.7%), nausea (5.1%), vomiting (5.1%), fatigue (1.6%), and diarrhea (5.1%). There was one treatment-related death caused by the perforation of the primary tumor. This patient refused surgery. Conclusions: DCS was a well-tolerated regimen with a high response rate in patients with advanced gastric cancer. Cisplatin at a dose of 60 mg/m2 was considered adequately effective. No significant financial relationships to disclose.

scholarly journals Cetuximab for the Treatment of Advanced Bronchioloalveolar Carcinoma (BAC): An Eastern Cooperative Oncology Group Phase II Study (ECOG 1504)

2011 ◽  
Vol 29 (13) ◽  
pp. 1709-1714 ◽  
Author(s):  
Suresh S. Ramalingam ◽  
Ju-Whei Lee ◽  
Chandra P. Belani ◽  
Seena C. Aisner ◽  
Jill Kolesar ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Smoking Status ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Bronchioloalveolar Carcinoma ◽  
Oncology Group ◽  
Ecog Performance Status ◽  
Kras Mutations

Purpose Inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have demonstrated modest anticancer activity in advanced bronchioloalveolar carcinoma (BAC). We conducted a phase II study to evaluate cetuximab for the treatment of advanced BAC. Patients and Methods Patients with advanced-stage pure BAC or adenocarcinoma with BAC features, fewer than two prior chemotherapy regimens, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 were eligible. Those with prior EGFR inhibitor therapy were excluded. Cetuximab was given as a weekly intravenous infusion at 250 mg/m2 after an initial loading dose of 400 mg/m2 in week 1. The primary end point was determination of response rate. EGFR and KRAS mutations were evaluated by pyrosequencing. Results Seventy-two patients were enrolled and 68 met eligibility requirements. Characteristics of patients included median age, 71 years; sex, 57% females; PS 0 or 1, 88% of patients; and smoking status, 19% never-smokers. Central pathology review confirmed the diagnosis in 45 of 49 available specimens. Approximately 50% of patients received more than two cycles of therapy (> 8 weeks). Skin rash was the most common toxicity (grade 3, 15%). The confirmed response rate was 7%, and stable disease was observed in 35%. The median survival and progression-free survival were 13 and 3.3 months, respectively. Only one of the six patients with an EGFR mutation and one of the seven patients with a KRAS mutation had a partial response. Conclusion Cetuximab was associated with modest efficacy in patients with advanced BAC, despite a low response rate. EGFR and KRAS mutations were not predictive of response to cetuximab.

Phase II study of cetuximab in combination with carboplatin and docetaxel for patients with advanced/metastatic non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7643-7643 ◽  
Author(s):  
C. P. Belani ◽  
S. Ramalingam ◽  
M. Schreeder ◽  
R. Steis ◽  
R. Guidice ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Single Agent ◽  
Stage Iiib ◽  
Duration Of Treatment ◽  
Ecog Performance Status

7643 Background: Cetuximab, a chimeric IgG1 monoclonal antibody against the external domain of the epidermal growth factor receptor (EGFR), has demonstrated single-agent activity against NSCLC. When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab exhibits synergistic interaction in preclinical studies. Therefore, we conducted a phase II study to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC. Methods: Chemotherapy-naive patients = 18 years with histologically/cytologically confirmed stage IIIB (w/ effusion) or stage IV NSCLC received cetuximab (400 mg/m2 on day 1 and 250 mg/m2 on days 8 and 15) plus docetaxel (75 mg/m2 on day 1) and carboplatin (AUC=6 on day 1) every 21 days for up to 6 cycles. Thereafter, patients without evidence of disease progression (CR/PR/SD) were continued on single-agent cetuximab (250 mg/m2/week) for a maximum of 1 year or until disease progression. The primary endpoint was response rate. Results: 81 patients were enrolled and 76 are evaluable for response. Patient characteristics included: gender male/female, 43/38; median age 63 years (range 42–83); ECOG performance status 0/1/, 31/50; and stage IIIB/IV- 5/76. The median number of cycles administered was 4 (range 1–6). The response rate (CR/PR) was 14.5% (95% CI, 7.5 to 24.4), with a median progression-free survival of 4.7 months and a median overall survival of 11 months. With combination therapy, the salient grade 3/4 events were neutropenia (28%), febrile neutropenia (3.8%), hypotension (4%), hypokalemia and hypomagnesemia (5%), hypersensitivity (1%), acne-like rash (3%), peripheral neuropathy (1%), and myalgia (1%). Twenty-five patients received maintenance therapy with single-agent cetuximab (median duration of treatment was 12 weeks) and this was well tolerated. Conclusions: This large multicenter phase II study of the novel combination of cetuximab with docetaxel and carboplatin shows promising efficacy for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. No significant financial relationships to disclose.

Phase II study: aclarubicin in advanced thyroid cancer

1988 ◽  
Vol 117 (4_Suppl) ◽  
pp. S144
Author(s):  
H. SAMONIGG ◽  
D.K. HOSSFELD ◽  
J. SPEHN ◽  
H. FILL ◽  
G. LEB
Keyword(s):  
Thyroid Cancer ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Advanced Thyroid Cancer

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

1998 ◽  
Vol 16 (5) ◽  
pp. 1948-1953 ◽  
Author(s):  
J Zalcberg ◽  
M Millward ◽  
J Bishop ◽  
M McKeage ◽  
A Zimet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2506-2506
Author(s):  
Anthony W. Tolcher ◽  
James Andrew Reeves ◽  
Meredith McKean ◽  
Bartosz Chmielowski ◽  
Joseph Thaddeus Beck ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Solid Tumors ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Nerve Sheath Tumor ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Ecog Performance Status ◽  
Multiple Tumor

2506 Background: Alrizomadlin (APG-115) restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Alrizomadlin also functions as a host immunomodulator and hence may restore antitumor activity in pts with cancers failing PD-1/PD-L1 blockade. Methods: This US multicenter trial assessed alrizomadlin combined with pembrolizumab in pts with unresectable/metastatic melanoma or advanced solid tumors that had failed I-O drugs; or pts with malignant peripheral nerve sheath tumor (MPNST), liposarcoma, or ATM mutant solid tumors that had failed any standard therapy. Eligible pts had ECOG performance status of 0-2 and no CNS metastases. The phase II study cohorts included pts with melanoma, NSCLC, solid tumor with ATM mutation, well-differentiated/dedifferentiated liposarcoma, urothelial carcinoma, and MPNST. Alrizomadlin was administered orally at 150 mg once every other day for 2 consecutive weeks with 1 week off and pembrolizumab at 200 mg via IV infusion for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 25, 2020, 84 pts had been treated in 6 cohorts: melanoma (n = 26), NSCLC (n = 23), ATM mutation (n = 9), liposarcoma (n = 14), urothelial (n = 9), and MPNST (n = 3). In the PD-1/PD-L1 inhibitor-failed melanoma cohort, there was 1 confirmed partial response (PR) out of 5 pts with uveal melanoma, 2 PR (1 confirmed and 1 unconfirmed) of 5 pts with mucosal melanoma, and 1 confirmed PR of 11 pts with cutaneous melanoma. ORR in the melanoma cohort was 17.4% (4/23 evaluable pts), and the disease control rate was 60.9% (14/23). In the MPNST cohort, 1 of 3 pts had an unconfirmed ongoing PR. In I-O drug-failed NSCLC (n = 14 evaluable) and urothelial (n = 5 evaluable) cohorts, each reported 1 confirmed PR. Common treatment (alrizomadlin or pembrolizumab)-related adverse events (TRAEs) (≥ 10%) were nausea (63.1%), thrombocytopenia (36.9%), vomiting (33.3%), fatigue (31.0%), decreased appetite (27.4%), diarrhea (21.4%), neutropenia (15.4%), and anemia (11.9%). Grade ≥ 3 TRAEs (≥ 5%) included thrombocytopenia (20.2%), neutropenia (14.2%), and anemia (8.3%). Eleven pts discontinued treatment due to AEs: 5 were treatment related, including 2 grade 4 thrombocytopenia, and 1 each of grade 2 vomiting, grade 2 fatigue, and grade 2 posterior reversible encephalopathy syndrome (PRES). Three treatment-related SAEs were PRES, pyrexia, and asthenia. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and may restore antitumor effects in pts with cancer resistant to or intolerant of I-O drugs, as suggested by preliminary antitumor activities in multiple tumor types. Internal study identifiers: APG-115-US-002; Keynote MK-3475-B66. Clinical trial information: NCT03611868.

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