A phase I, open-label, dose-escalation trial of BI 1701963 as monotherapy and in combination with trametinib in patients with KRAS mutated advanced or metastatic solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3651-TPS3651 ◽  
Author(s):  
Eelke Gort ◽  
Melissa Lynne Johnson ◽  
Jimmy J. Hwang ◽  
Shubham Pant ◽  
Ulrich Dünzinger ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Retinal Pigment ◽  
Objective Response ◽  
Active Form ◽  
Open Label ◽  
Retinal Pigment Epithelial Detachment ◽  
Kras Mutations ◽  
Part C ◽  
Recist 1.1 ◽  
Number Of Patients

TPS3651 Background: Activating mutations of KRAS drive many types of cancer. Activation of KRAS relies on guanine nucleotide exchange factors, such as SOS1, to mediate exchange of GDP for GTP. BI 1701963 is a small-molecule protein–protein interaction inhibitor that prevents the interaction between KRAS and SOS. Binding of BI 1701963 to the catalytic site of SOS1 inhibits binding of SOS1 to RAS–GDP, thereby hindering the exchange from RAS–GDP (inactive form) to RAS–GTP (active form). In preclinical studies this has been shown to lead to cytostasis in cancer cells addicted to KRAS signaling. Methods: NCT04111458 is a first-in-human trial of BI 1701963 in patients aged ≥18 years with tumors harboring KRAS mutations. Primary objectives are to determine the maximum tolerated dose (MTD) and recommended Phase II dose of BI 1701963 as monotherapy and in combination with trametinib, based on dose-limiting toxicities (DLTs). Secondary objectives are to evaluate safety, tolerability, pharmacokinetics/-dynamics and preliminary efficacy. The study will have two arms (mono- and combination therapy), and be divided into dose escalation (Part A), confirmation (Part B) and expansion (Part C, combination only) phases. Inclusion criteria include activating KRAS mutation, ≥1 evaluable lesion (RECIST 1.1), ECOG PS ≤1 and adequate organ function. Exclusion criteria include history of: RAS, MAPK or SOS1 targeting therapies; retinal vein occlusion; retinal pigment epithelial detachment; and decreased cardiac function. Parts B and C will be conducted in patients with advanced NSCLC. Treatment will continue until confirmed clinical benefit, defined toxicities, or withdrawal of consent. The primary endpoints are: Part A, the MTD, and the number of patients with DLTs during Cycle 1; Part B (monotherapy), the number of patients with DLTs; Part C, objective response (OR, RECIST 1.1). Starting doses of BI 1701963 in Part A will be 50 mg once daily (QD) orally (monotherapy) and 100 mg QD (combination, once proved safe as monotherapy) and will be escalated until the MTD is reached. The starting dose of trametinib will be 1 mg QD, escalated to the MTD or a max. of 2 mg QD. Dose cohorts will include ≥3 patients, with two therapeutic relevant doses (TRDs) established in each arm. In Part B, patients will be randomized to groups receiving one of the TRDs. If an OR is observed at a TRD in the combination arm, additional patients will be recruited into expansion cohorts receiving the relevant dose. As of Feb 11, 2020 three patients have been treated. Clinical trial information: NCT04111458 .

A phase Ia/Ib, open label, multicenter, dose-escalation study of BI 907828 (MDM2-p53 antagonist) in adult patients with advanced or metastatic solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3166-TPS3166 ◽  
Author(s):  
Curtis Robert Chong ◽  
Todd Michael Bauer ◽  
Scott Andrew Laurie ◽  
Manish R. Patel ◽  
Noboru Yamamoto ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Treatment Cycle ◽  
Objective Response ◽  
Locally Advanced ◽  
Negative Regulator ◽  
Recommended Dose ◽  
Open Label ◽  
Number Of Patients ◽  
Phase 1B

TPS3166 Background: Inactivation of tumor protein 53 (TP53) is a central mechanism of tumors to promote survival and proliferation. The murine double minute 2 ( MDM2) oncogene is the primary cellular negative regulator of TP53. Small molecule inhibitors of the MDM2-p53 interaction are currently being evaluated in clinical trials as new anti-cancer drugs, and clinical data published to date support the rationale to target MDM2-amplified tumors. BI 907828 is a potent MDM2-p53 antagonist that has shown efficacy in mouse models of human cancer. Methods: NCT03449381 is a Phase 1a/1b, open-label, multicenter, dose-escalation trial of BI 907828 in patients aged ≥18 years with advanced/metastatic solid tumors. Primary objectives of the Phase 1a (dose-escalation) part are to determine: the maximum tolerated dose (MTD) of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle; the recommended dose for expansion (RDE); safety and tolerability. Patients in Arm A will receive one dose of BI 907828 every 21 days, and patients in Arm B one dose on Days 1 and 8, every 28 days. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD) [GDF-15 induction in plasma], and preliminary anti-tumor activity. Primary endpoints are the number of patients with DLTs during the first treatment cycle, and the MTD. Phase 1a will include ≈50 evaluable patients with locally advanced or metastatic solid tumors with either a known TP53 wild type (wt) status or unknown TP53 status, regardless of MDM2 amplification status at the time of study entry. The main objectives of Phase 1b (expansion cohorts) are to assess efficacy, safety, and PK profiles at the RDE, and to determine the recommended dose for Phase 2. The primary endpoint is objective response, where best response is determined according to RECIST v1.1, or RANO criteria for patients with glioblastoma. Phase 1b will include up to 150 evaluable patients with TP53 wt tumors, assigned to four different cohorts, including non-squamous NSCLC, soft tissue sarcoma, glioblastoma, urothelial carcinoma, and solid tumors with brain metastases. As of 8th February 2019, 11 patients have been enrolled. Clinical trial information: NCT03449381.

A phase III, randomized, open-label, study (CONTACT-02) of cabozantinib plus atezolizumab versus second novel hormone therapy (NHT) in patients (pts) with metastatic, castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS190-TPS190
Author(s):  
Neeraj Agarwal ◽  
Arun Azad ◽  
Joan Carles ◽  
Simon Chowdhury ◽  
Bradley Alexander McGregor ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Soft Tissue ◽  
Objective Response ◽  
Specific Antigen ◽  
Phase Iii ◽  
Disease Stage ◽  
Open Label ◽  
Phase 3 ◽  
Recist 1.1 ◽  
Cancer Aggressiveness

TPS190 Background: Cabozantinib inhibits multiple tyrosine kinases, including MET, VEGFR, RET, and TAM kinases (Tyro3, AXL, MER), involved in tumor growth and angiogenesis, and whose mutations and expression are associated with prostate cancer aggressiveness and poor prognosis. Targeting these kinases with cabozantinib may promote an immune permissive tumor environment and may enhance response to immune checkpoint inhibitors. In the ongoing phase 1b COSMIC-021 study of pts with solid tumors, cabozantinib plus the PD-L1 inhibitor atezolizumab, showed preliminary meaningful clinical activity in soft tissue disease and a tolerable safety profile for 44 pts with mCRPC (Agarwal et al., ASCO 2020; abstract 5564). We present the study design of a phase 3 trial of cabozantinib plus atezolizumab versus second NHT in pts with mCRPC. Methods: This randomized, open-label, controlled phase 3 study (NCT04446117) evaluates the efficacy and safety of cabozantinib plus atezolizumab versus second NHT (abiraterone or enzalutamide) in pts with mCRPC who previously received one NHT to treat metastatic castration-sensitive PC (mCSPC), non-metastatic CRPC (M0 CRPC), or mCRPC. Additional eligibility criteria include histologically or cytologically confirmed adenocarcinoma of the prostate, measurable visceral disease or measurable extrapelvic adenopathy per RECIST 1.1 by investigator, prostate specific antigen progression and/or soft-tissue disease progression, ECOG 0 or 1, and age ≥18 years. Key exclusion criteria include prior nonhormonal therapy for mCRPC and uncontrolled significant illness. Eligible pts (N = 580) are randomized 1:1 to receive cabozantinib (40 mg PO QD) + atezolizumab (1200 mg IV Q3W) vs abiraterone (1000 mg PO QD) + prednisone (5 mg PO BID) or enzalutamide (160 mg PO QD). Designated NHT will differ from previous NHT taken. Randomization is stratified by: liver metastasis (yes, no), prior docetaxel treatment for mCSPC (yes, no), and disease stage for which the first NHT was given (mCSPC, M0 CRPC, mCRPC). Treatment will continue until there is no longer clinical benefit as determined by the treating investigator, unacceptable toxicity, or consent withdrawal. The multiple primary endpoints are progression-free survival per RECIST 1.1 by blinded independent radiology committee (BIRC) and overall survival. Additional endpoints include objective response rate per RECIST 1.1 by BIRC, safety, correlation of biomarkers with outcomes, quality of life and pharmacokinetics. Patient enrollment is ongoing. Clinical trial information: NCT04446117.

Phase II study of cabozantinib (cabo) combined with pembrolizumab (pembro) in metastatic or recurrent gastric and gastroesophageal adenocarcinoma (GEC) to overcome resistance to checkpoint inhibitors.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS253-TPS253
Author(s):  
Farshid Dayyani ◽  
Chloe Thomas ◽  
Gwendolyn Ung ◽  
Thomas H Taylor
Keyword(s):  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Objective Response ◽  
Unmet Need ◽  
Primary Objective ◽  
Phase 2 ◽  
Open Label ◽  
Secondary Resistance ◽  
Phase 2 Trial ◽  
Number Of Patients

TPS253 Background: GEC is the third leading cause of cancer mortality and the fifth most common malignancy worldwide. Fluoropyrimidine and platinum-based combinations are the most commonly used 1L treatment regimens. There are few standard treatment options after 1st line regimens. In the 3L+ GEC Keynote-059 trial, objective response rate (ORR) with Pembro was 15.5% in PD-L1(+) vs. 6.4% in PD-L1(-) tumors. While the responses were durable, the 6-months PFS (6-PFS) was only 14.1% and the median PFS was 2.0 mo. This highlights the remaining unmet need for the majority of patients who either are refractory or develop disease progression following treatment with PD-1 inhibitors in GEC. Cabo plus checkpoint inhibitors have shown clinical benefit in various cancers including hepatocellular, renal cell (RCC), urothelial and castration-resistant prostate cancers. In the CheckMate-9ER trial, Cabo+Nivolumab improved both OS and PFS vs sunitinib in 1L RCC. In patients with RCC who had progression on anti-PD1 inhibitor treatment, Cabo showed promising activity with an ORR of 33% and DCR of 79% (ESMO 2018, abstract 3793). Hypothesis: Based on preclinical and clinical observations, Cabo might contribute to overcoming primary or secondary resistance to PD-1 blockade in GEC. Methods: Prospective, open label, non-randomized phase 2 trial. Eligibility: Diagnosis of GEC, 2+ line of treatment including previous fluoropyrimidine/platinum, ECOG 0-2, adequate organ function, prior checkpoint inhibitor if tumor PD-L1 CPS≥10%. Treatment: Cabozantinib 40mg PO daily, Pembrolizumab 200 mg IV on day 1 of 21d cycle. Primary objective: Feasibility of the combination and estimate of efficacy. Primary endpoint:PFS-6. Secondary objectives: OS, ORR, adverse events. Total number of patients to be enrolled N = 27. Current enrollment (Sep 2020) N = 10. Statistics: If the PFS-6 is > 25%, the study would be regarded as positive, in which case it is planned to expand patient enrollment into a larger single arm phase 2 trial with additional sites to establish the efficacy of the regimen. Clinical trial information: NCT04164979.

A phase Ib/II, multicenter, open-label, dose-escalation, and dose-expansion study evaluating trastuzumab deruxtecan (T-DXd, DS-8201) monotherapy and combinations in patients with HER2-overexpressing gastric cancer (DESTINY-Gastric03).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS261-TPS261
Author(s):  
Yelena Y. Janjigian ◽  
Natasha Viglianti ◽  
Feng Liu ◽  
Ariadna Mendoza-Naranjo ◽  
Liz Croydon
Keyword(s):  
Gastric Cancer ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Metastatic Gastric Cancer ◽  
Her2 Status ◽  
Open Label ◽  
Phase 1B

TPS261 Background: For patients (pts) with HER2-overexpressing metastatic gastric cancer, trastuzumab + chemotherapy is a standard first-line option but provides only a modest overall survival (OS) benefit vs chemotherapy. T-DXd is an antibody-drug conjugate consisting of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and a membrane-permeable topoisomerase I inhibitor payload. Results from a phase 1 trial showed promising antitumor activity (confirmed objective response rate [ORR], 43.2%) in pts with heavily pretreated HER2+ metastatic gastric cancer who received T-DXd (5.4 or 6.4 mg/kg; Shitara K, et al. Lancet Oncol. 2019;20:827-836). Here we describe the phase 1b/2 DESTINY-Gastric03 trial (NCT04379596) evaluating T-DXd monotherapy and combinations in pts with HER2-overexpressing gastric cancer. Methods: This is an open-label, multicenter, 2-part, phase 1b/2 study in pts with HER2-overexpressing (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization positive) locally advanced, unresectable or metastatic gastric or gastroesophageal junction cancer. In part 1 (dose escalation), pts who had received prior trastuzumab-containing therapy will be assigned to 1 of 5 arms: (1) T-DXd + 5-fluorouracil (5-FU); (2) T-DXd + capecitabine (C); (3) T-DXd + durvalumab; (4) T-DXd + 5-FU or C + oxaliplatin (Ox); or (5) T-DXd + 5-FU or C + durvalumab. In part 2 (dose expansion), pts with no prior treatment for metastatic disease will be randomized across 4 arms: (1) T-DXd; (2) trastuzumab + 5-FU or C + Ox or cisplatin; (3) T-DXd + 5-FU or C ± Ox; or (4) T-DXd + 5-FU or C + durvalumab. In part 2, pts will be stratified by HER2 status. Primary endpoints are safety, determination of recommended phase 2 doses (part 1), and investigator-assessed confirmed ORR per RECIST v1.1 (part 2). Secondary endpoints include confirmed ORR (part 1), disease control rate, duration of response, progression-free survival (all per investigator), OS, safety (part 2), pharmacokinetics, and immunogenicity. Clinical trial information: NCT04379596.

Lazertinib, a 3rd generation EGFR-TKI, in patients with EGFR-TKI resistant NSCLC: Updated results of phase I/II Study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9037-9037 ◽  
Author(s):  
Myung-Ju Ahn ◽  
Ji-Youn Han ◽  
Sang-We Kim ◽  
Ki Hyeong Lee ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Egfr Mutations ◽  
Duration Of Treatment ◽  
Open Label ◽  
T790m Mutation ◽  
Dose Levels ◽  
Egfr Tki

9037 Background: Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. We report the updated results from a Phase I/II study of lazertinib (NCT03046992). Methods: Patients with advanced and metastatic NSCLC who had progressed after treatment with standard EGFR-TKIs with/without asymptomatic brain metastases (BM) were enrolled in an open-label, multicenter, phase I/II study with dose-escalation and expansion cohorts. Lazertinib was administered once daily at doses between 20 to 320 mg in a 21-day cycle. Patients were assessed for safety, tolerability and efficacy. T790M mutation was required in the dose-expansion cohorts. Results: As of 26 Nov 2018, a total of 127 patients were enrolled. The dose-escalation cohort included 38 patients administered with 20 to 320 mg across 7 dose levels, and 89 patients in the dose-expansion cohort were administered with 40 to 240 mg across 5 dose levels. No dose-limiting toxicities were observed. The median duration of treatment was 9.7 months and 58 patients are still ongoing. The objective response rate (ORR) was 60% in all patients, 64% in T790M+ patients, and 37% in T790M- patients by investigators assessment. In BM patients with measurable lesion (n = 14), the intracranial ORR was 50%. The median progression-free survival (PFS) was 8.1 months in all patients, 9.5 months in T790M+ patients, and 5.4 months in T790M- patients. Subgroup analysis showed that ORR was 65% and PFS was 12.2 months in T790M+ patients with ≥ 120 mg (n = 62). The most common treatment-emergent adverse events (TEAEs) were pruritus (27%), rash (24%), constipation (20%), decreased appetite (19%) and diarrhea (14%). TEAEs leading to dose discontinuation were observed in 3% of patients. Drug related TEAEs of grade ≥ 3 was observed in 3% of the patients. Conclusions: Lazertinib was safe, well-tolerated and exhibits promising systemic and intracranial antitumor activity in EGFR T790M+ NSCLC patients. Dose extension cohorts in the 1st and 2nd line settings are underway at 240 mg dose. Clinical trial information: NCT03046992.

A phase I dose-escalation and expansion study of intratumoral CV8102 as single-agent or in combination with anti-PD-1 antibodies in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3096-3096
Author(s):  
Thomas Eigentler ◽  
Franz G Bauernfeind ◽  
Jürgen C. Becker ◽  
Peter Brossart ◽  
Michael Fluck ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Dose Escalation ◽  
Single Agent ◽  
Objective Response ◽  
Study Drug ◽  
Tumor Growth Inhibition ◽  
Open Label ◽  
Dose Levels

3096 Background: CV8102 is a non-coding, non-capped RNA that activates the innate (via TLR7/8, RIG-I) and adaptive immunity dose-dependently. CV8102 injected intratumorally (i.t.), as a single agent or combined with systemic anti-PD-1 antibody (Ab) led to tumor growth inhibition in animal models and showed synergism with PD-1 blockade. Methods: An open-label, cohort-based, dose escalation and expansion study in patients with advanced cutaneous melanoma (cMEL), cutaneous squamous cell carcinoma (cSCC), head and neck squamous cell carcinoma (hnSCC) or adenoid cystic carcinoma (ACC) is ongoing investigating i.t. CV8102 as single agent and in combination with anti-PD-1 antibodies. [NCT03291002]. Results: As of December 2019, 23 patients in the cohort A (single agent) and 13 patients in cohort C (combination with anti-PD-1 Ab) were exposed to at least one dose of CV8102 at dose levels of 25-600 µg (single agent) and 25-450 µg (combination). No dose limiting toxicities (DLTs) were observed within the first two weeks of study drug treatment. Most frequent TEAEs were G1/2 fatigue, fever, chills and headache. 4 (17%) patients (pts) in cohort A and 3 (23%) pts in cohort C experienced related G3 TEAEs that were manageable with supportive treatment (liver enzyme increases (3), abscess at injection site (1), hypertension (1), asymptomatic elevation of pancreatic enzymes (2)). In cohort A, 2 cMEL patients experienced an objective response according to RECIST 1.1 (1 CR in a PD-1 naïve pt and 1 PR in a PD-1 refractory pt) and 2 further pts (cMEL, hnSCC) showed SD with shrinkage of tumor lesions. Conclusions: CV8102 i.t. was well tolerated without dose limiting toxicities to date and showed evidence of single agent activity. Updated results on safety, efficacy and serum biomarkers will be presented. Clinical trial information: NCT03291002 .

AGENT: An open-label phase III study of arfolitixorin versus leucovorin in modified FOLFOX-6 for first-line treatment of metastatic colorectal cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS268-TPS268
Author(s):  
Heinz-Josef Lenz ◽  
Peter Gibbs ◽  
Sebastian Stintzing ◽  
Gerald W. Prager ◽  
Peter Nygren ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Objective Response ◽  
Metabolic Activation ◽  
Phase Iii ◽  
First Line ◽  
Open Label ◽  
Eligibility Criteria ◽  
Number Of Patients ◽  
Secondary Endpoints

TPS268 Background: 5-fluorouracil (5FU), in combination with folates, is an established cornerstone of metastatic colorectal cancer (mCRC) treatment. All folates currently approved for mCRC need to be metabolically activated to [6R]-5,10-methylenetetrahydrofolic acid ([6R]-MTHF), the active thymidylate synthase co-substrate that potentiates the effect of 5FU. Arfolitixorin does not require multi-step metabolic activation, and may produce higher, and less inter- and intraindividually variable, concentrations of [6R]-MTHF than leucovorin. Methods: The phase III AGENT trial (NCT03750786) is a randomized, multicenter, parallel-group study comparing the efficacy of arfolitixorin versus leucovorin in mCRC patients treated with first-line 5FU, oxaliplatin, and bevacizumab. Patients are randomized (1:1) to the investigational arm (arfolitixorin + 5FU + oxaliplatin [ARFOX] + bevacizumab) or the comparator arm (leucovorin + 5FU + oxaliplatin [modified FOLFOX-6] + bevacizumab), and treated until disease progression based on RECIST 1.1 criteria. Recruitment is ongoing, and aims to randomize 440 patients in 18 months. Eligibility criteria include non-resectable mCRC; eligibility for 5FU, oxaliplatin, and bevacizumab therapy; ECOG PS 0 or 1. The study will be conducted across approximately 100 sites in Australia, Austria, Canada, France, Germany, Greece, Japan, Spain, Sweden, and USA. The primary endpoint is objective response rate. Key secondary endpoints are progression-free survival and duration of response. Additional secondary endpoints include overall survival, quality of life, safety and tolerability, and number of patients undergoing curative metastasis resection. A translational program will evaluate expression levels of several folate metabolism- and transportation-related genes in mCRC tumor biopsies to determine their relationship to treatment outcome. A broad array of genes will analyzed, including ATP-binding cassette C3 (ABCC3) transporter, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), proton-coupled folate transporter (PCFT), and serine hydroxymethyltransferase 1 (SHMT1). Interim data are expected in mid 2020. Clinical trial information: NCT03750786.

scholarly journals Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor

2014 ◽  
Vol 32 (33) ◽  
pp. 3697-3704 ◽  
Author(s):  
Douglas B. Johnson ◽  
Keith T. Flaherty ◽  
Jeffrey S. Weber ◽  
Jeffrey R. Infante ◽  
Kevin B. Kim ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Rapid Progression ◽  
Open Label ◽  
Safety And Efficacy ◽  
Mek Inhibition ◽  
Part C ◽  
Inhibitor Treatment

Purpose Preclinical and early clinical studies have demonstrated that initial therapy with combined BRAF and MEK inhibition is more effective in BRAFV600-mutant melanoma than single-agent BRAF inhibitors. This study assessed the safety and efficacy of dabrafenib and trametinib in patients who had received prior BRAF inhibitor treatment. Patients and Methods In this open-label phase I/II study, we evaluated the pharmacology, safety, and efficacy of dabrafenib and trametinib. Here, we report patients treated with combination therapy after disease progression with BRAF inhibitor treatment administered before study enrollment (part B; n = 26) or after cross-over at progression with dabrafenib monotherapy (part C; n = 45). Results In parts B and C, confirmed objective response rates (ORR) were 15% (95% CI, 4% to 35%) and 13% (95% CI, 5% to 27%), respectively; an additional 50% and 44% experienced stable disease ≥ 8 weeks, respectively. In part C, median progression-free survival (PFS) was 3.6 months (95% CI, 2 to 4), and median overall survival was 11.8 months (95% CI, 8 to 25) from cross-over. Patients who previously received dabrafenib ≥ 6 months had superior outcomes with the combination compared with those treated < 6 months; median PFS was 3.9 (95% CI, 3 to 7) versus 1.8 months (95% CI, 2 to 4; hazard ratio, 0.49; P = .02), and ORR was 26% (95% CI, 10% to 48%) versus 0% (95% CI, 0% to 15%). Conclusion Dabrafenib plus trametinib has modest clinical efficacy in patients with BRAF inhibitor–resistant melanoma. This regimen may be a therapeutic strategy for patients who previously benefited from BRAF inhibitor monotherapy ≥ 6 months but demonstrates minimal efficacy after rapid progression with BRAF inhibitor therapy.

scholarly journals Single-arm, open-label, dose-escalation phase I study to evaluate the safety of a herbal medicine SH003 in patients with solid cancer: a study protocol

BMJ Open ◽  
2018 ◽  
Vol 8 (8) ◽  
pp. e019502 ◽  
Author(s):  
Chunhoo Cheon ◽  
Sohyeon Kang ◽  
Youme Ko ◽  
Mia Kim ◽  
Bo-Hyoung Jang ◽  
...  
Keyword(s):  
Herbal Medicine ◽  
Adverse Events ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
University Hospital ◽  
Solid Cancer ◽  
Open Label ◽  
Major Health Problem ◽  
Number Of Patients ◽  
Label Dose

IntroductionCancer is a major health problem worldwide and the leading cause of death in many countries. The number of patients with cancer and socioeconomic costs of cancer continues to increase. SH003 is a novel herbal medicine consisting ofAstragalus membranaceus,Angelica gigasandTrichosanthes Kirilowii Maximowicz. Preclinical studies have shown that SH003 has therapeutic anticancer effects. The aim of this study is to determine the maximum tolerated dose of SH003 in patients with solid cancers.Methods and analysisThis study is an open-label, dose-escalation trial evaluating the safety and tolerability of SH003. The traditional 3+3 dose-escalation design will be implemented. Patients with solid cancers will be recruited. According to dose level, the patients will receive one to four tablets of SH003, three times a day for 3 weeks. Toxicity will be evaluated using common terminology criteria for adverse events (CTCAE). Dose-limiting toxicities are defined as grade 3 or higher adverse events based on CTCAE. The maximum tolerated dose will be determined by the highest dose at which no more than one of six patients experiences dose-limiting toxicity.Ethics and disseminationThis study has been approved by the institutional review board of the Ajou University Hospital (reference AJIRB-MED-CT1-16-311). The results of this study will be disseminated through a scientific journal and a conference.Trial registration numberNCT03081819; Pre-results.

A phase Ia/Ib, dose-escalation/expansion study of BI 907828 in combination with BI 754091 and BI 754111 in patients (pts) with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3660-TPS3660
Author(s):  
Anthony W. Tolcher ◽  
Navid Hafez ◽  
Noboru Yamamoto ◽  
Jaehong Park ◽  
Rolf Grempler ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Dose Escalation ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Wild Type ◽  
Phase Ib ◽  
Multiple Tumor ◽  
Recist 1.1 ◽  
Secondary Endpoints

TPS3660 Background: Preclinical data show that the combination of a murine double minute 2–tumor protein 53 (MDM2–TP53) antagonist with anti-PD-1 and anti-LAG3 antibodies produces an anti-tumor effect in multiple tumor types. This Phase Ia/Ib study aims to determine the safety, recommended dose for expansion (RDE), and preliminary efficacy of BI 907828, a MDM2–TP53 antagonist, with BI 754091, an anti-PD-1 antibody, and BI 754111, an anti-LAG-3 antibody, in a variety of TP53 wild-type cancers. Methods: In Phase Ia (dose escalation), ~30 pts with a confirmed diagnosis of any unresectable, advanced/metastatic solid tumor, irrespective of TP53 mutation status, will be enrolled. Pts will receive one dose of BI 907828 every 21 days (Q3W), at a starting dose of 10 mg orally, plus BI 754091 and BI 754111 (240 mg and 600 mg, respectively, Q3W, intravenously). Dose escalation will be guided by a Bayesian Logistic Regression Model with overdose control. The primary endpoint is the maximum-tolerated dose of BI 907828 based on dose-limiting toxicities (DLTs) during the first treatment cycle. Secondary endpoints include pharmacokinetics and DLTs in the treatment period (to determine the RDE). In Phase Ib (dose expansion), pts with previously treated, unresectable, advanced/metastatic TP53 wild-type tumors with ≥1 measurable target lesion will be enrolled into four expansion cohorts (1: NSCLC; 2: melanoma; 3: well-differentiated/dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma; 4: hepatocellular carcinoma). The RDE of BI 907828 will be administered with fixed doses of BI754091 and BI 754111 (Q3W). In the NSCLC cohort only, pts will be randomized to one of three arms: RDE of BI 907828 + 240 mg BI 754091 + 600 mg BI 754111 (arm A, 32 pts); 240 mg BI 754091 + 600 mg BI 754111 (arm B, 32 pts); RDE of BI 907828 + 240 mg BI 754091 (arm C, 16 pts). The primary endpoint is objective response (OR, per RECIST 1.1). Secondary endpoints include OR (per iRECIST), disease control (per RECIST 1.1 and iRECIST), progression-free survival (PFS), PFS rate at 12 and 24 weeks (cohort 3), and safety. Phase Ib will include at least 140 evaluable pts (80 pts in cohort 1 and 20 pts each in cohorts 2–4). Clinical trial information: NCT03964233 .

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