Phase I dose escalation trial (ARQ 197–111) evaluating combination of selective c-Met inhibitor ARQ 197 and erlotinib

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3549-3549 ◽  
Author(s):  
I. Laux ◽  
J. Goldman ◽  
R. Just ◽  
K. Brady ◽  
J. Li ◽  
...  
Keyword(s):  
Drug Interaction ◽  
Phase I ◽  
Dose Escalation ◽  
Sinus Bradycardia ◽  
Study Drug ◽  
Competitive Inhibitor ◽  
Tumor Cell Migration ◽  
Egfr Inhibition ◽  
Arq 197 ◽  
Drug Drug Interaction

3549 Background: ARQ197 (A) is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Phase I data for ARQ 197 monotherapy is previously reported. Recent evidence suggests c-Met promotes resistance to EGFR-inhibition by driving ERBB3 (HER3)-dependent PI3K activation. Dual EGFR-Met inhibition is now proposed as a strategy for overcoming resistance to EGFR-inhibition. Methods: Patients (pts) were enrolled in a sequential-cohort dose-escalation trial seeking to define safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity of A in combination with 150 mg daily oral erlotinib (E). Oral A was administered at escalating doses of 120, 240, and 360 mg bid. Intra-patient dose escalation was allowed in the absence of dose-limiting toxicity (DLT) through 1 cycle of therapy (21 days). Results: 25 pts (10 F/15 M; mean 60.5 yrs) received EA combination with starting A dose of 120 (8 pts), 240 (4 pts), and 360 (13 pts) mg bid. PK data reveal linear kinetics through 360 bid and no evidence of drug-drug interaction. Adverse events (AEs) considered related to combination therapy were reported in 13 (52%) of pts incl.sinus bradycardia (5 pts), fatigue (5 pts), rash (4 pts), itching (3 pts), and diarrhea (3 pts). 2 pts experienced related serious AEs incl. neutropenia (360 bid) and sinus bradycardia (240 bid). 1 death occurring on-study was considered unrelated to study drug. 9/10 evaluable pts demonstrated disease stabilization (SD) as their best RECIST response (5.9–27.1+ wks). Tumor regressions (2.3%-19.4%) were observed in 4/10 evaluable pts. Of note, 3/3 evaluable pts with NSCLC achieved SD for durations (14–32 wks) exceeding median PFS in BR.21 (9.7 wks). Conclusions: Continuous therapy with EA combination appears well tolerated and without drug-drug interaction. While no formal MTD was identified, a phase 2 combination dose (R2PD) of 360 mg bid A + 150 mg daily E is recommended. This RP2D is currently being investigated in an ongoing randomized trial comparing EA to E monotherapy in 2nd/3rd line NSCLC. [Table: see text]

Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3548-3548 ◽  
Author(s):  
T. Mekhail ◽  
T. Rich ◽  
L. Rosen ◽  
F. Chai ◽  
Z. Semic-Suka ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Safety Data ◽  
Dose Escalation Study ◽  
Tumor Cell Migration ◽  
Drug Concentrations ◽  
Arq 197 ◽  
Favorable Safety

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [Table: see text]

A Phase I/II Study Of Cytarabine Or Azacitidine In Combination With Tosedostat In Older Patients With AML Or High-Risk MDS

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2698-2698 ◽  
Author(s):  
Courtney D. DiNardo ◽  
Hagop M Kantarjian ◽  
Farhad Ravandi ◽  
Marina Konopleva ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Escalation ◽  
Older Patients ◽  
Progressive Disease ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Study Drug ◽  
Starting Dose ◽  
Wbc Count

Abstract Background The aminopeptidase inhibitor tosedostat is an orally bioavailable novel chemotherapeutic, functioning through enzymatic blockade of intracellular protein degradation and re-synthesis. Encouraging results have been observed with tosedostat monotherapy in Phase I and II trials of relapsed and refractory elderly AML patients. Aims This Phase I/II trial explores the safety, tolerability and activity of tosedostat in combination with cytarabine or azacitidine in older patients with AML or high-risk MDS. Methods Eligibility includes age >60 years, performance status of 0-2, with relapsed/refractory AML or high-risk MDS having failed prior hypomethylating agent (HMA) and/or lenalidomide therapy. All subjects received tosedostat 120mg orally once daily for 28 day cycles, with either subcutaneous (SQ) cytarabine at starting dose of 7.5mg twice daily for 10 days, or azacitidine (AZA) IV/SQ at starting dose of 50mg/m2 daily for 7 days, per investigator’s choice. A modified 3+3 dose escalation design was used in the Phase I portion to identify the maximum tolerated dose independently for both arms. Escalation to the predefined target dose levels of 10mg SQ cytarabine twice daily for 10 days, or azacitidine 75mg/m² IV/SQ daily for 7 days per 28 day cycle was achieved. Dose escalation to 180mg daily tosedostat was allowable for patients not achieving a CR after 4 weeks on therapy. Results From November 2012 to April 2013, the Phase I portion completed enrollment with a total of 18 patients (10 with AZA, 8 cytarabine). Six patients discontinued prior to completion of cycle 1 for reasons other than study-drug related toxicity or progressive disease and were replaced; they are considered as non-responders in the primary efficacy analysis. Median age was 73 (range 60-81), and 56% were male. 13 patients (72%) had secondary or therapy-related AML, of which 11 (61%) had prior MDS. The median number of prior treatments for MDS and/or AML was 2 (range 1-6), and 11 (61%) had received prior HMA therapy. Median white blood cell (WBC) count at study start was 5x10⁹/L (range 0.3 – 44.2), with median peripheral blood blasts of 27% (range 0-95%), and bone marrow blasts 57% (range 6-90%). The majority (61%) of patients had complex cytogenetics or abnormal cytogenetics involving chromosome 5 and/or 7; six patients (33%) had diploid cytogenetics. Molecular analysis identified 1 FLT3-ITD, 3 DNMT3A, 2 JAK2 V617F, 2 NRAS, 2 KRAS, and 1 IDH1 mutation. Median duration on study was 49 days (range 13 – 254), with median overall survival (OS) of 3.1 months (range 0.4-8.5) and an overall response rate (ORR) of 33% (CR/CRp/MLFS 17%, PR 17%). ORR was 50% (CR/CRp/MLFS 25%, PR 25%) in fully evaluable patients remaining on study for >28 days. Median OS for patients with CR/CRp/MLFS and PR was 7.3 and 3.5 months, respectively, while OS for unevaluable patients or those with progressive disease was 29 days. On univariate analysis, the presence of a diploid karyotype (p=0.001) or WBC count <4x10⁹/L (p=0.036) associated with an improved ORR. The most common non-hematologic toxicities regardless of attribution (all %; grade >3) included pleural and pericardial effusions (72%; 0%), dyspnea (67%; 0%), peripheral edema (61%; 6%), pneumonia (56%; 50%), fatigue (50%; 0%), diarrhea (50%; 0%), and cough (39%; 0%). Additional cardiac toxicities included systolic dysfunction (17%; 6%), QTc prolongation (50%; 6%) and myocardial infarction (MI) (11%; 11%). One fatal acute coronary event on cycle 2, day 2 of tosedostat 180mg and AZA 75mg/m² was considered possibly related to study drug. Conclusions The combination of tosedostat with low-dose cytarabine or azacitidine appears effective in a population with an overall very poor prognosis. Additional safety and efficacy evaluations are ongoing. Updated results and follow-up will be presented at the annual meeting. Disclosures: No relevant conflicts of interest to declare.

Phase I dose escalation study of TG02 in patients with advanced hematologic malignancies.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6577-6577 ◽  
Author(s):  
Gail J. Roboz ◽  
Hanna Jean Khoury ◽  
Jamile M. Shammo ◽  
Mary Syto ◽  
Francis Burrows ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Intensive Therapy ◽  
Study Drug ◽  
Underlying Disease ◽  
Median Number ◽  
Open Label ◽  
Dose Escalation Study ◽  
Multikinase Inhibitor ◽  
Dose Levels

6577 Background: TG02 is a novel multikinase inhibitor with a unique spectrum of activity, targeting both the cell cycle regulatory cyclin-dependent kinases (CDKs) 1 and 2 and the transcriptional regulators CDKs 7 and 9. TG02 also inhibits the emerging oncogenic MAPK ERK5 and the DNA damage response mediator CDK5. TG02 kills primary blasts from a variety of hematologic cancers and is curative in the MV4-11 model of FLT3-mutant AML. Methods: This is a first-in-man,single arm, open label, phase I dose escalation trial. The primary endpoints are dose-limiting toxicity (DLT), maximally tolerated dose (MTD ) and recommended phase 2 dose (RP2D). Patients (pts) ≥ 18 years with advanced hematological malignancies or newly diagnosed AML pts ≥ 65 years unfit for intensive therapy were enrolled onto daily (A) and intermittent (B, 5 days on 2 days off X 2 weeks) schedules. Pts had acceptable organ function and ECOG PS 1-2. Definition of DLT was G3-4 AST or ALT ≥7 days, G4 AST or ALT, G4 hyperbilirubinemia, any other NCI CTC G3-4 events not due to underlying disease. Dose levels on arm A were 10mg to 70mg and 15mg-150 mg on arm B. Results: Forty-five pts have received at least one dose of study drug. Median age was 66 years (range, 37-87) and 80% were ECOG 0-1. Disease types enrolled included: AML (80%), high-risk MDS (22%), and CML-BC (3%). The median number of previous regimens was 3 (range, 1-12). The MTD on arm A was defined at 50 mg daily based on 2 DLTs at the 70mg dose level (G4 hyperbilirubinemia, G4 fatigue). Enrollment to arm B has competed dose levels 15 (N=3), 30 (N=3), 50 (N=3), 70 (N=3), 100mg (N=3), and enrollment at 150mg is ongoing without DLT to date. Common drug related adverse events were nausea (42%), vomiting (23%), fatigue (18%), decreased appetite (15%), constipation and diarrhea (13% each). Preliminary PK demonstrated dose proportional increases in exposure and a T1/2 , supporting once daily dosing. Conclusions: The MTD for TG02 has been determined for the daily schedule at 50mg. Enrollment continues on the intermittent schedule. Schedules of every other day and week on/week off dosing will also be evaluated.

First-in-human phase I dose-escalation study of the oral selective C-met inhibitor EMD 1204831 in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3107-3107
Author(s):  
Hesham M. Amin ◽  
Gerald Steven Falchook ◽  
Siqing Fu ◽  
David S. Hong ◽  
Apostolia Maria Tsimberidou ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Cell Surface Receptor ◽  
Advanced Solid Tumors ◽  
Multiple Dosing ◽  
Dose Escalation Study ◽  
Tumor Cell Migration ◽  
Met Inhibitor ◽  
Anti Tumor Activity

3107^ Background: The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor, are implicated in tumor cell migration, invasion, survival, and proliferation. EMD 1204831 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods: This is a phase I, first-in-human clinical trial with escalating doses of EMD 1204831 (NCT01110083). The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (Pd), and preliminary anti-tumor activity. Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3+3 dose-escalation scheme, successive cohorts of patients were treated with twice daily (BID) oral EMD 1204831 in 21-day cycles. Pd markers were evaluated in paired tumor biopsies (phospho-c-Met). Results: Until 31 December 2011, 30 patients were enrolled and treated. The dose was escalated in successive cohorts starting from 50 mg BID up to 1400 mg BID. After first (single) administration, median Cmax and AUC0–12 values increased with dose. At higher doses, a decrease in exposure of EMD 1204831 was noted after multiple dosing, potentially caused by autoinduction of the compound’s metabolism. Further dose escalation was discontinued, and no further patients were enrolled. One dose-limiting toxicity (DLT) of grade (G) 3 pancreatitis, considered as a serious adverse event (AE), was observed at 400 mg BID. No other DLTs or treatment-related serious AEs were observed. The remaining treatment-related AEs of G2 or higher included G3 and G2 lipase elevation (n=1 for each grade), G2 upper abdominal pain (n=2), G2 gastroesophageal reflux disease (n=2), and G2 constipation (n=1). Twenty-five patients (83%) had no drug-related toxicity greater than G1. Of 29 patients evaluable for anti-tumor activity, 3 had stable disease lasting for at least 4 months. Conclusions: Due to potential autoinduction of the compound’s metabolism, dose escalation was discontinued before an MTD was reached. Final safety, PK, and clinical tumor response results will be presented.

A phase I dose escalation study of PCUR-101 in men with metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16517-e16517 ◽  
Author(s):  
Christos Kyriakopoulos ◽  
Channing Judith Paller ◽  
Ajit Verma ◽  
Karim Kader ◽  
Jeff Kittrelle ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Human Study ◽  
Study Drug ◽  
Maximum Tolerated Dose ◽  
Drug Formulation ◽  
Clinical Activity ◽  
Second Phase ◽  
Castration Resistant Prostate Cancer ◽  
Dose Escalation Study

e16517 Background: The combination of PCUR-101 (a synthetic form of the plant-derived medicinal agent, plumbagin) and surgical castration caused regression of androgen dependent tumors in mice. These promising pre-clinical results led to this first-in-human study of PCUR-101 in combination with androgen deprivation therapy (ADT) in men with metastatic, castrate resistant PCa (mCRPC). Methods: The goal of this phase I multicenter trial was to determine the safety profile, maximum tolerated dose (MTD), recommended phase II dose, clinical activity, and pharmacokinetic (PK) parameters of PCUR-101. A 3 + 3 dose escalation design was employed. Patients (pts) in cohorts of 3 were treated with escalating doses of PCUR-101 (50 mg – 200 mg) orally once daily continuously. Cycles were 28 days. Exploratory correlates of IL-6 and urine polyamines were also included. Results: 12 pts (median age 75 [range 63-86]) with mCRPC on ADT were treated in the dose escalation cohorts. No DLTs were observed during treatment and the MTD was not reached. The most frequent adverse events (AEs) included diarrhea (11 pts; all grade 1 or 2), nausea (7 pts; all grade 1 or 2), vomiting (4 pts; all grade 1 or 2) and constipation (3 pts; all grade 1 or 2). No objective responses were observed but 1 pt had PSA decrease by > 50%. Pts remained on study treatment for a median of 10 weeks (range 3-32 weeks). 5 pts, with stable disease, remain on active treatment. PK data could not be fully evaluated due to issues with the PK assay. Analyses of IL-6 and putrescine levels in pt samples indicate that, as compared to no treatment, PCUR-101 treatment in each cycle was associated with decreases in their levels. Reasons for treatment discontinuation included disease progression (n = 4), adverse event (n = 1; nausea and vomiting), subject withdrawal (n = 1), and investigator or sponsor decision (n = 1). After treating 12 pts, the sponsor decided to stop the trial in order to reformulate the study drug to allow for higher dosing and to redevelop the PK assay. Conclusions: At the doses evaluated, PCUR-101 combined with ADT was seen to be safe and may prolong disease stability in men with mCRPC. A second phase I study is planned using a new drug formulation and PK assay. Clinical trial information: NCT03137758.

Biomarker analysis (CTC and ctDNA/RNA) of GT0918 (Proxalutamide) new AR blocker in phase I mCRPC patients with dose escalation.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 186-186
Author(s):  
Karl Zhou ◽  
Phoebe Zhang ◽  
Youzhi Tong ◽  
Liandong Ma
Keyword(s):  
Phase I ◽  
Clinical Outcomes ◽  
Dose Escalation ◽  
Tumor Biology ◽  
Study Drug ◽  
Resistance Mechanisms ◽  
Development Programs ◽  
Dose Escalation Study ◽  
Biomarker Analysis ◽  
Monitoring Treatment

186 Background: AR blockade is an important treatment option for mCRPC in clinic and GT0918 is a new chemical entity of AR blocker in 2nd generation. A phase I dose escalation study was planned in pts with mCRPC progressed on multiple lines of SoC and experimental therapies. Daily oral administration of GT0918 has shown better clinical outcomes in 400mg and 500mg cohorts with no comprised toxicities. To study the tumor biology in response to study drug in clinical setting, CTC and cfDNA/RNA based biomarkers were explored. Methods: Pts with histologically confirmed mCRPC who progressed on enza, abi, docetaxel, etc were enrolled and treated with GT0918 continuously until PD, intolerable toxicity or withdraw. Blood samples were collected at baseline, on study drug every 8 wks during the trial and pts with ≥ 3 blood test samples were qualified for various assays for CTCs and cfDNA/RNA via EPIC and PredicinePlus platforms. Results: Total 40 pts were orally administrated GT0918 with dose increasing 50, 100, 200, 300, 400, 500 and 600 mg daily and shown well tolerated with mild to moderate toxicities. Pts received GT0918 over 16 weeks were run biomarkers in Predicine and/or Epic platforms. ctDNA/RNA based variants and CTCs are all detectable in selected pts samples. AR splicing variants (AR-V3 and AR-V7), AR hotspot mutations (W742C, T878A and S889G) and amplifications were detected and shown interesting trends with the clinical outcomes. Both exploratory biomarkers and CTCs suggested higher doses of GT0918 resulted in better clinical outcomes. Conclusions: This is a preliminary study to explore genomic alterations and the CTC enumeration in late stage of mCRPC pts in response to GT0918 treatment with dose increase. As non-invasive assays, both CTC and ctDNA/RNA assays provided valuable molecular insights for monitoring treatment effects besides PSA and imaging scan. Early detection of possible drug sensitivity/resistance mechanisms will facilitate clinical development programs. More patients will be tested in phase II study GT0918 in mCRPC progressed on either abiraterone or enzalutamide. Clinical trial information: NCT02826772. [Table: see text]

Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
R. Sangha ◽  
C. Ho ◽  
L. Beckett ◽  
D. H. Lau ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Gene Copy ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Egfr Inhibition ◽  
Biomarker Analysis

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]

Sign in / Sign up

Export Citation Format

Share Document