A phase 1b study of the MET inhibitor capmatinib combined with cetuximab in patients with MET-positive colorectal cancer who had progressed following anti-EGFR monoclonal antibody treatment.

Abstract:

:Background Overcoming resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in patients with KRAS wildtype (WT) metastatic colorectal cancer (mCRC) could help meet the needs of patients with limited treatment options. Methods In this phase 1b study, patients with N/KRAS WT, MET-positive mCRC who had progressed following anti-EGFR mAb treatment received escalating oral doses of capmatinib (150, 300, and 400 mg) twice daily plus weekly intravenous cetuximab (at the approved dose). The primary objective was to establish a recommended dose for expansion (RDE) of capmatinib in combination with cetuximab. Safety, preliminary activity, pharmacokinetics, and pharmacodynamics were also explored. Results Thirteen patients were enrolled. No patients experienced a dose-limiting toxicity at investigated doses; the RDE was established as capmatinib 400 mg twice daily plus cetuximab. All patients experienced adverse events (AEs) suspected to be related to the study treatment. Five patients (38.5%) reported study-drug-related AEs of grade 3/4 in severity. No patients achieved a complete or partial response according to RECIST v1.1; however, tumor shrinkage of 29-44% was observed in 4 patients. Conclusions Capmatinib plus cetuximab was well tolerated. Preliminary signs of activity were observed. Further investigation is warranted to obtain efficacy data and refine predictive biomarkers of response. Clinical trial registration NCT02205398.

journal_name

Invest New Drugs

authors

Delord JP,Argilés G,Fayette J,Wirth L,Kasper S,Siena S,Mesia R,Berardi R,Cervantes A,Dekervel J,Zhao S,Sun Y,Hao HX,Tiedt R,Vicente S,Myers A,Siu LL

doi

10.1007/s10637-020-00928-z

subject

Has Abstract

pub_date

2020-12-01 00:00:00

pages

1774-1783

issue

6

eissn

0167-6997

issn

1573-0646

pii

10.1007/s10637-020-00928-z

journal_volume

38

pub_type

杂志文章
  • Feasibility of olanzapine, multi acting receptor targeted antipsychotic agent, for the prevention of emesis caused by continuous cisplatin- or ifosfamide-based chemotherapy.

    abstract::Background To determine the feasibility and efficacy of olanzapine, which is approved by the Pharmaceuticals and Medical Devices Agency as multi acting receptor targeted antipsychotic agent of the thienobenzodiazepine class, for prevention of chemotherapy-induced nausea and vomiting (CINV) in patients undergoing conti...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1007/s10637-017-0487-3

    authors: Bun S,Yonemori K,Akagi T,Noguchi E,Shimoi T,Shimomura A,Yunokawa M,Shimizu C,Fujiwara Y,Makino Y,Hayashi Y,Tamura K

    更新日期:2018-02-01 00:00:00

  • Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors.

    abstract:BACKGROUND:To explore the activity of lapatinib with a novel trial design focused on the drug target rather than on histology. METHODS:Patients with HER2 amplified gastro-esophageal, bladder, ovarian, or uterine tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1,500 mg PO daily....

    journal_title:Investigational new drugs

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1007/s10637-010-9541-0

    authors: Galsky MD,Von Hoff DD,Neubauer M,Anderson T,Fleming M,Nagarwala Y,Mahoney JM,Midwinter D,Vocila L,Zaks TZ

    更新日期:2012-04-01 00:00:00

  • Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion.

    abstract::The limiting toxicity of low dose continuous infusion 5-fluorouracil (200-300 mg/m2/day) is often palmar-plantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42%-82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00216925

    authors: Fabian CJ,Molina R,Slavik M,Dahlberg S,Giri S,Stephens R

    更新日期:1990-02-01 00:00:00

  • Metabolic carbonyl reduction of anthracyclines - role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents.

    abstract::Anthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to seconda...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,评审

    doi:10.1007/s10637-017-0443-2

    authors: Piska K,Koczurkiewicz P,Bucki A,Wójcik-Pszczoła K,Kołaczkowski M,Pękala E

    更新日期:2017-06-01 00:00:00

  • Dual inhibition of MEK1/2 and EGFR synergistically induces caspase-3-dependent apoptosis in EGFR inhibitor-resistant lung cancer cells via BIM upregulation.

    abstract::Epidermal growth factor receptor (EGFR) gene mutations activate the KRAS-RAF-MEK-ERK pathway in lung cancer cells. EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib induce apoptosis of cancer cells, but prolonged treatment is often associated with acquired resistance. Here, we identified a novel MEK1/2 inhibito...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-013-0030-0

    authors: Song JY,Kim CS,Lee JH,Jang SJ,Lee SW,Hwang JJ,Lim C,Lee G,Seo J,Cho SY,Choi J

    更新日期:2013-12-01 00:00:00

  • A retrospective pooled analysis of trabectedin safety in 1,132 patients with solid tumors treated in phase II clinical trials.

    abstract:PURPOSE:To summarize the safety experience obtained from phase II clinical trials conducted with trabectedin as single-agent therapy in patients with advanced solid tumors. METHODS:This retrospective analysis includes 1,132 patients exposed to trabectedin in 19 phase II trials carried out between February 1999 and Apr...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-011-9662-0

    authors: Le Cesne A,Yovine A,Blay JY,Delaloge S,Maki RG,Misset JL,Frontelo P,Nieto A,Jiao JJ,Demetri GD

    更新日期:2012-06-01 00:00:00

  • Multicenter phase II study of the AKT inhibitor MK-2206 in recurrent or metastatic nasopharyngeal carcinoma from patients in the mayo phase II consortium and the cancer therapeutics research group (MC1079).

    abstract:BACKGROUND:This study investigated the activity of MK-2206, an AKT inhibitor, in metastatic or recurrent nasopharyngeal carcinoma (NPC). METHOD:Oral MK-2206 at a dose of 200 mg was administered on days 1, 8, 15 and 22 of a 28-day cycle until progression. Plasma EBV DNA clearance during the first month of treatment was...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,多中心研究

    doi:10.1007/s10637-015-0264-0

    authors: Ma BB,Goh BC,Lim WT,Hui EP,Tan EH,Lopes Gde L,Lo KW,Li L,Loong H,Foster NR,Erlichman C,King AD,Kam MK,Leung SF,Chan KC,Chan AT

    更新日期:2015-08-01 00:00:00

  • Evaluation of gemcitabine in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a Southwest Oncology Group phase II study.

    abstract::A phase II trial of gemcitabine (Gemzar), a nucleoside analogue with broad activity in solid tumors, was performed in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. A total of 26 eligible patients were registered to receive a dose of 1250 mg/m2 weekly for 3 weeks, followed by a 1 w...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1023/a:1010657609609

    authors: Samlowski WE,Gundacker H,Kuebler JP,Giguere JK,Mills GM,Schuller DE,Ensley JF

    更新日期:2001-01-01 00:00:00

  • A phase I safety and pharmacokinetic study of ABT-263 in combination with carboplatin/paclitaxel in the treatment of patients with solid tumors.

    abstract::Bcl-2 family proteins are the key regulators of the intrinsic apoptotic pathway, controlling the point-of no-return and setting the threshold to engage the death machinery in response to chemical damage. Bcl-2 proteins have emerged as attractive targets for anti-cancer drug development. Navitoclax is a selective, pote...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-014-0116-3

    authors: Vlahovic G,Karantza V,Wang D,Cosgrove D,Rudersdorf N,Yang J,Xiong H,Busman T,Mabry M

    更新日期:2014-10-01 00:00:00

  • Phase II trial of uracil/tegafur (UFT) plus leucovorin in patients with advanced hepatocellular carcinoma.

    abstract:UNLABELLED:Although UFT 300 mg/m2/day and leucovorin 90 mg/day administered orally in divided doses administered every 8 hours for 28 days repeated every 35 days could be administered safely to patients with advanced hepatomas and good performance status, this combination and schedule has limited activity in treating a...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1023/a:1006104217137

    authors: Mani S,Schiano T,Garcia JC,Ansari RH,Samuels B,Sciortino DF,Tembe S,Shulman KL,Baker A,Benner SE,Vokes EE

    更新日期:1998-01-01 00:00:00

  • Effect of alisertib, an investigational aurora a kinase inhibitor on the QTc interval in patients with advanced malignancies.

    abstract::Aims A primary objective of this study was to investigate the effect of single and multiple doses of alisertib, an investigational Aurora A kinase inhibitor, on the QTc interval in patients with advanced malignancies. The dose regimen used was the maximum tolerated dose which was also the recommended phase 3 dose (50 ...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-017-0498-0

    authors: Zhou X,Nemunaitis J,Pant S,Bauer TM,Patel M,Sarantopoulos J,Craig Lockhart A,Goodman D,Huebner D,Mould DR,Venkatakrishnan K

    更新日期:2018-04-01 00:00:00

  • Dual modulation of JNK and Akt signaling pathways by chaetoglobosin K in human lung carcinoma and ras-transformed epithelial cells.

    abstract::Chaetoglobosin K (ChK) is a natural product that inhibits anchorage-dependent and anchorage-independent growth of ras-transformed cells, prevents tumor-promoter disruption of cell-cell communication, and reduces Akt activation in tumorigenic cells. This study demonstrates how ChK modulates the JNK pathway in ras-trans...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-012-9883-x

    authors: Ali A,Sidorova TS,Matesic DF

    更新日期:2013-06-01 00:00:00

  • Prolonged infusion gemcitabine: a clinical phase I study at low- (300 mg/m2) and high-dose (875 mg/m2) levels.

    abstract::Gemcitabine (GEM) is a novel nucleoside analogue with a unique mechanism of action. Preliminary studies have shown a mild, schedule-dependent toxic profile with a broad range of MTDs and promising antitumor activity in various solid tumors. This phase I study describes the infusion length-effect relationships of low- ...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1023/a:1005817024382

    authors: Pollera CF,Ceribelli A,Crecco M,Oliva C,Calabresi F

    更新日期:1997-01-01 00:00:00

  • Phase II trial with oral idarubicin in advanced breast cancer.

    abstract::Idarubicin, a new analogue of daunorubicin, was administered to 27 patients with advanced breast cancer in a phase II trial. The drug was given orally at a dose of 30-35 mg/m2 every 3 weeks. Twenty-two patients were evaluable for response. All evaluable patients were previously treated with one or more chemotherapeuti...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00172014

    authors: Lopez M,Di Lauro L,Papaldo P,Lazzaro B,Ganzina F,Di Pietro N

    更新日期:1986-01-01 00:00:00

  • Sphingosine-1-phosphate: a potential therapeutic agent against human breast cancer.

    abstract::Sphingosine-1-phosphate (S1P) is an important regulator of cancer development and progression. Its cellular concentration is controlled predominantly by sphingosine kinase (SK) and sphingosine-1-phosphate lyase (SPL). In the current study we showed that mRNA expressions for both SK and SPL were up-regulated throughout...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-009-9375-9

    authors: Ling B,Chen L,Alcorn J,Ma B,Yang J

    更新日期:2011-04-01 00:00:00

  • Phase I study of sunitinib plus S-1 and cisplatin in Japanese patients with advanced or metastatic gastric cancer.

    abstract:BACKGROUND:This phase I, dose-finding study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib plus S-1/cisplatin in Japanese patients with advanced/metastatic gastric cancer. PATIENTS AND METHODS:Patients received oral sunitinib on a continuous daily dosing (CDD)...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-013-9948-5

    authors: Boku N,Muro K,Machida N,Hashigaki S,Kimura N,Suzuki M,Lechuga M,Miyata Y

    更新日期:2014-04-01 00:00:00

  • A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors.

    abstract::Purpose Preclinical evidence suggests dichloroacetate (DCA) can reverse the Warburg effect and inhibit growth in cancer models. This phase 1 study was undertaken to assess the safety, recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile of oral DCA in patients with advanced solid tumors. Patients and Meth...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-015-0221-y

    authors: Chu QS,Sangha R,Spratlin J,Vos LJ,Mackey JR,McEwan AJ,Venner P,Michelakis ED

    更新日期:2015-06-01 00:00:00

  • 3-Deazaguanine: report of a phase I trial and drug-related cardiac toxicity.

    abstract::3-Deazaguanine (Dezaguanine), a purine antimetabolite, was evaluated in a phase I trial in 42 patients with advanced solid tumors. Dezaguanine was given as a weekly intravenous infusion for three consecutive weeks of a four-week cycle. The dose ranged from 30 to 2000 mg/m2; no consistent dose-limiting hematologic or g...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1007/BF00198593

    authors: Margolin K,Doroshow J,Leong L,Akman S,Carr B,Odujinrin O,Flanagan B,Grove W,DeLap R,Goldberg D

    更新日期:1990-11-01 00:00:00

  • Effect of ketoconazole on the pharmacokinetics of axitinib in healthy volunteers.

    abstract:OBJECTIVE:Axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, is metabolized primarily by cytochrome P450 (CYP) 3A with minor contributions from CYP1A2, CYP2C19, and glucuronidation. Co-administration with CYP inhibitors may increase systemic expos...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,随机对照试验

    doi:10.1007/s10637-010-9511-6

    authors: Pithavala YK,Tong W,Mount J,Rahavendran SV,Garrett M,Hee B,Selaru P,Sarapa N,Klamerus KJ

    更新日期:2012-02-01 00:00:00

  • The new isothiocyanate 4-(methylthio)butylisothiocyanate selectively affects cell-cycle progression and apoptosis induction of human leukemia cells.

    abstract::We investigated proliferation and apoptosis induction in Jurkat T-leukemia cells by the new isothiocyanate 4-(methylthio)butylisothiocyanate (MTBITC). To help elucidate whether the effects of MTBITC are specific for cancer cells, we tested MTBITC on freshly isolated, non-transformed human peripheral T lymphocytes. The...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1023/B:DRUG.0000011788.19754.54

    authors: Fimognari C,Nüsse M,Iori R,Cantelli-Forti G,Hrelia P

    更新日期:2004-04-01 00:00:00

  • Phase I dose escalation and pharmacokinetic evaluation of two different schedules of LY2334737, an oral gemcitabine prodrug, in patients with advanced solid tumors.

    abstract:BACKGROUND:This Phase-I-study aimed to determine the recommended Phase-II-dosing-schedule of LY2334737, an oral gemcitabine prodrug, in patients with advanced/metastatic solid tumors. Pharmacokinetics, cytokeratin-18 (CK18) levels, genetic polymorphisms, and antitumor activity were additionally evaluated. METHODS:Pati...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-015-0286-7

    authors: Faivre SJ,Olszanski AJ,Weigang-Köhler K,Riess H,Cohen RB,Wang X,Myrand SP,Wickremsinhe ER,Horn CL,Ouyang H,Callies S,Benhadji KA,Raymond E

    更新日期:2015-12-01 00:00:00

  • Phase I trial of 5-fluorouracil by 24-hour infusion weekly.

    abstract::A novel schedule of 5-fluorouracil administration has been developed for biochemical modulation studies. In combination with the pyrimidine synthesis inhibitor PALA, 5-fluorouracil has been given as a 24-hour infusion, repeated weekly: a dose of 2600 mg/m2 is well tolerated. To identify a suitable dose of 5-fluorourac...

    journal_title:Investigational new drugs

    pub_type: 临床试验,杂志文章

    doi:10.1007/BF00874152

    authors: Haas NB,Hines JB,Hudes GR,Johnston N,Ozols RF,O'Dwyer PJ

    更新日期:1993-05-01 00:00:00

  • Two randomized, double-blind, placebo-controlled, dose-escalation phase 1 studies evaluating BTH1677, a 1, 3-1,6 beta glucan pathogen associated molecular pattern, in healthy volunteer subjects.

    abstract:BACKGROUND:BTH1677 is a beta glucan pathogen associated molecular pattern (PAMP) currently being investigated as a novel cancer therapy. Here, the initial safety and pharmacokinetic (PK) results of BTH1677 in healthy subjects are reported. SUBJECTS AND METHODS:In the Phase 1a single-dosing study, subjects were randomi...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,随机对照试验

    doi:10.1007/s10637-016-0325-z

    authors: Halstenson CE,Shamp T,Gargano MA,Walsh RM,Patchen ML

    更新日期:2016-04-01 00:00:00

  • Phase II study of esorubicin (4'-deoxydoxorubicin) in advanced epithelial carcinoma of the ovary: a Gynecologic Oncology Group study.

    abstract::Twenty-six patients with advanced, measurable epithelial carcinoma of the ovary were treated with 76 courses of esorubicin at doses ranging from 20-30 mg/m2 every 3 weeks. All patients are evaluable for toxicity and response. All patients had received prior therapy including radiation therapy in 9, non-anthracycline c...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00173763

    authors: McGuire WP,Blessing JA,Berman ML

    更新日期:1989-11-01 00:00:00

  • An international, multicenter phase II trial of bortezomib in patients with hepatocellular carcinoma.

    abstract:BACKGROUND AND RATIONALE:Bortezomib (PS-341, VELCADE®) is a selective inhibitor of the 26S proteasome, an integral component of the ubiquitin-proteasome pathway. This phase II study evaluated the activity and tolerability of bortezomib in unresectable hepatocellular carcinoma (HCC) patients. METHODS:The primary endpoi...

    journal_title:Investigational new drugs

    pub_type: 杂志文章,多中心研究

    doi:10.1007/s10637-010-9532-1

    authors: Kim GP,Mahoney MR,Szydlo D,Mok TS,Marshke R,Holen K,Picus J,Boyer M,Pitot HC,Rubin J,Philip PA,Nowak A,Wright JJ,Erlichman C

    更新日期:2012-02-01 00:00:00

  • Phase I clinical study of nafazatrom.

    abstract::Nafazatrom, a synthetic pyrazolinone derivative, has been shown to have substantial antitumor activity in vitro and antitumor and antimetastatic activity in experimental animal systems. The drug has produced no substantial toxicity in preclinical studies and during limited human trials. A phase I clinical trial with t...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00179592

    authors: Hortobagyi GN,Papadoupoulos NE,Frye D,Ajani J,Reuben JM

    更新日期:1986-01-01 00:00:00

  • Nafazatrom: clonogenic in-vitro assessment of activity against human malignancies.

    abstract::Nafazatrom was tested against a variety of human malignancies with the human tumor stem cell assay at one or more of the following concentrations: 1, 10, 25, and 100 micrograms/ml X 1 h or 0.05, 0.5, or 5 micrograms/ml by continuous exposure. Major (greater than or equal to 70%) inhibition was noted in 7/52 adenocarci...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00173781

    authors: Haas CD,Kyle GW,Crissman JD,Schaldenbrand MF

    更新日期:1984-01-01 00:00:00

  • Posterior reversible encephalopathy syndrome induced by enzalutamide in a patient with castration-resistant prostate cancer.

    abstract::Posterior reversible encephalopathy syndrome (PRES) is a clinical/radiological syndrome characterized by symptoms that can include seizure, headache, impaired vision and hypertension, and can be confirmed by magnetic resonance imaging. Numerous reports have emerged that describe PRES in cancer patients. The list of me...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-014-0193-3

    authors: Crona DJ,Whang YE

    更新日期:2015-06-01 00:00:00

  • Phase II trial of acivicin in patients with advanced epithelial ovarian carcinoma. A Gynecologic Oncology Group Study.

    abstract::Twenty-four evaluable patients with epithelial ovarian cancer resistant to primary therapy, or relapsing after response to initial therapy, were treated with acivicin utilizing a daily X 5 schedule. One patient achieved a partial response lasting five months; the remaining 23 patients showed no objective response. Pro...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/BF00172016

    authors: McGuire WP,Blessing JA,DiSaia PJ,Buchsbaum HJ

    更新日期:1986-01-01 00:00:00

  • Generation and tumor recognition properties of two human monoclonal antibodies specific to cell surface anionic phospholipids.

    abstract::Phosphatidylserine (PS) and other anionic phospholipids, which become exposed on the surface of proliferating endothelial cells, tumor cells and certain leukocytes, have been used as targets for the development of clinical-stage biopharmaceuticals. One of these products (bavituximab) is currently being investigated in...

    journal_title:Investigational new drugs

    pub_type: 杂志文章

    doi:10.1007/s10637-015-0248-0

    authors: Bujak E,Pretto F,Neri D

    更新日期:2015-08-01 00:00:00