Karim A. Benhadji

Taiho Oncology (United States)

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Sandrine Faivre

Hôpital Saint-Louis

ÉR

Éric Raymond

Hôpital Paris Saint-Joseph

Antoine Hollebecque

Institut Gustave Roussy

Jordi Rodón

The University of Texas MD Anderson Cancer Center

Ann Cleverly

UCB Pharma (United Kingdom)

Ivelina Gueorguieva

Eli Lilly (United Kingdom)

Robin Kate Kelley

University of California, San Francisco

Maria Serova

Sechenov University

Claire Smith

AstraZeneca (United Kingdom)

Funda Meric‐Bernstam

The University of Texas MD Anderson Cancer Center

Cooperative Institutions

Eli Lilly (United States)

158

John Wiley & Sons (United States)

112

Hudson Institute

109

Liechtenstein Institute

103

Inserm

Assistance Publique – Hôpitaux de Paris

The University of Texas MD Anderson Cancer Center

Harvard University

Université Paris Cité

Centre National de la Recherche Scientifique

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Data from Futibatinib, an Irreversible FGFR1–4 Inhibitor, in Patients with Advanced Solid Tumors Harboring FGF/FGFR Aberrations: A Phase I Dose-Expansion Study

Funda Meric‐Bernstam Rastislav Bahleda Cinta Hierro Marc Sanson John Bridgewater

<div>AbstractFutibatinib, a highly selective, irreversible FGFR1–4 inhibitor, was evaluated in a large multihistology phase I dose-expansion trial that enrolled 197 patients with advanced solid tumors. Futibatinib demonstrated an objective response rate (ORR) of 13.7%, with responses in a broad spectrum of tumors (cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer) bearing both known and previously uncharacterized FGFR1–3 aberrations. The greatest activity was observed in FGFR2 fusion/rearrangement–positive intrahepatic cholangiocarcinoma (ORR, 25.4%). Some patients with acquired resistance to a prior FGFR inhibitor also experienced responses with futibatinib. Futibatinib demonstrated a manageable safety profile. The most common treatment-emergent adverse events were hyperphosphatemia (81.2%), diarrhea (33.5%), and nausea (30.4%). These results formed the basis for ongoing futibatinib phase II/III trials and demonstrate the potential of genomically selected early-phase trials to help identify molecular subsets likely to benefit from targeted therapy.Significance:This phase I dose-expansion trial demonstrated clinical activity and tolerability of the irreversible FGFR1–4 inhibitor futibatinib across a broad spectrum of FGFR-aberrant tumors. These results formed the rationale for ongoing phase II/III futibatinib trials in cholangiocarcinoma, breast cancer, gastroesophageal cancer, and a genomically selected disease-agnostic population.<a href="https://aacrjournals.org/cancerdiscovery/article/doi/10.1158/2159-8290.CD-12-2-ITI" target="_blank">This article is highlighted in the In This Issue feature, p. 275</a></div>

Tolerability

10.1158/2159-8290.c.6549325.v1

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Efficacy and safety of trifluridine/tipiracil in older and younger patients with metastatic gastric or gastroesophageal junction cancer: subgroup analysis of a randomized phase 3 study (TAGS)

Gastric Cancer (2022)

Kohei Shitara Toshihiko Doi Hisashi Hosaka Peter Thuss‐Patience Armando Santoro

Abstract Background Trifluridine and tipiracil (FTD/TPI) demonstrated survival benefit vs placebo and manageable safety in previously treated patients with metastatic gastric/gastroesophageal junction cancer (mGC/GEJC) in the randomized, placebo-controlled, phase 3 TAGS study. This subgroup analysis of TAGS examined efficacy/safety outcomes by age. Methods In TAGS, patients with mGC/GEJC and ≥ 2 prior therapies were randomized (2:1) to receive FTD/TPI 35 mg/m 2 or placebo, plus best supportive care. A preplanned subgroup analysis was performed to evaluate efficacy and safety outcomes in patients aged < 65, ≥ 65, and ≥ 75 years. Results Among 507 randomized patients ( n = 337 FTD/TPI; n = 170 placebo), 55%, 45%, and 14% were aged < 65, ≥ 65, and ≥ 75 years, respectively. Overall survival hazard ratios for FTD/TPI vs placebo were 0.67 (95% CI 0.51–0.89), 0.73 (95% CI 0.52–1.02), and 0.67 (95% CI 0.33–1.37) in patients aged < 65, ≥ 65, and ≥ 75 years, respectively. Regardless of age, patients receiving FTD/TPI experienced improved progression-free survival and stayed longer on treatment than those receiving placebo. Among FTD/TPI-treated patients, frequencies of any-cause grade ≥ 3 adverse events (AEs) were similar across age subgroups (80% each), although grade ≥ 3 neutropenia was more frequent in older patients [40% (≥ 65 and ≥ 75 years); 29% (< 65 years)]; AE-related discontinuation rates did not increase with age [14% (< 65 years), 12% (≥ 65 years), and 12% (≥ 75 years)]. Conclusions The results of this subgroup analysis show the efficacy and tolerability of FTD/TPI treatment regardless of age in patients with mGC/GEJC who had received 2 or more prior treatments.

Tolerability

Subgroup analysis

Discontinuation

10.1007/s10120-021-01271-9

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Citations (10)

Leveraging historical data into oncology development programs: Two case studies of phase 2 Bayesian augmented control trial designs

Pharmaceutical Statistics (2020)

Claire Smith Zachary M. Thomas Nathan Enas Katharine Thorn Michael Lahn

SUMMARY Leveraging historical data into the design and analysis of phase 2 randomized controlled trials can improve efficiency of drug development programs. Such approaches can reduce sample size without loss of power. Potential issues arise when the current control arm is inconsistent with historical data, which may lead to biased estimates of treatment efficacy, loss of power, or inflated type 1 error. Consideration as to how to borrow historical information is important, and in particular, adjustment for prognostic factors should be considered. This paper will illustrate two motivating case studies of oncology Bayesian augmented control (BAC) trials. In the first example, a glioblastoma study, an informative prior was used for the control arm hazard rate. Sample size savings were 15% to 20% by using a BAC design. In the second example, a pancreatic cancer study, a hierarchical model borrowing method was used, which enabled the extent of borrowing to be determined by consistency of observed study data with historical studies. Supporting Bayesian analyses also adjusted for prognostic factors. Incorporating historical data via Bayesian trial design can provide sample size savings, reduce study duration, and enable a more scientific approach to development of novel therapies by avoiding excess recruitment to a control arm. Various sensitivity analyses are necessary to interpret results. Current industry efforts for data transparency have meaningful implications for access to patient‐level historical data, which, while not critical, is helpful to adjust for potential imbalances in prognostic factors.

Research Design

10.1002/pst.1990

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Citations (5)

1000MO A phase I/II, open-label study of the novel checkpoint IGSF8 inhibitor GV20-0251 in patients with advanced solid tumors

Annals of Oncology (2024)

Kristopher Wentzel J. Peguero S. Kummar Patricia LoRusso Janice M. Mehnert

10.1016/j.annonc.2024.08.1059

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Evaluation of the Cytochrome P450 3A and P‐glycoprotein Drug‐Drug Interaction Potential of Futibatinib

Clinical Pharmacology in Drug Development (2023)

Ikuo Yamamiya Allen Hunt Toru Takenaka Daryl Sonnichsen Mark Mina

Futibatinib, a selective, irreversible fibroblast growth factor receptor 1-4 inhibitor, is being investigated for tumors harboring FGFR aberrations and was recently approved for the treatment of FGFR2 fusion/rearrangement-positive intrahepatic cholangiocarcinoma. In vitro studies identified cytochrome P450 (CYP) 3A as the major CYP isoform in futibatinib metabolism and indicated that futibatinib is likely a P-glycoprotein (P-gp) substrate and inhibitor. Futibatinib also showed time-dependent inhibition of CYP3A in vitro. Phase I studies investigated the drug-drug interactions of futibatinib with itraconazole (a dual P-gp and strong CYP3A inhibitor), rifampin (a dual P-gp and strong CYP3A inducer), or midazolam (a sensitive CYP3A substrate) in healthy adult participants. Compared with futibatinib alone, coadministration of futibatinib with itraconazole increased futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 51% and 41%, respectively, and coadministration of futibatinib with rifampin lowered futibatinib mean peak plasma concentration and area under the plasma concentration-time curve by 53% and 64%, respectively. Coadministration of midazolam with futibatinib had no effect on midazolam pharmacokinetics compared with midazolam administered alone. These findings suggest that concomitant use of dual P-gp and strong CYP3A inhibitors/inducers with futibatinib should be avoided, but futibatinib can be concomitantly administered with other drugs metabolized by CYP3A. Drug-drug interaction studies with P-gp-specific substrates and inhibitors are planned.

CYP3A

P-glycoprotein

Midazolam

10.1002/cpdd.1259

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Safety and clinical activity of the Notch inhibitor, crenigacestat (LY3039478), in an open-label phase I trial expansion cohort of advanced or metastatic adenoid cystic carcinoma

Investigational New Drugs (2019)

Caroline Even Ulrik Lassen Jaime R. Merchan Christophe Le Tourneau J-C. Soria

Summary Background Deregulated Notch signaling is implicated in multiple cancers. The phase I trial (I6F-MC-JJCA) investigated the safety and anti-tumor activity of crenigacestat (LY3039478), a selective oral Notch inhibitor, in an expansion cohort of patients with adenoid cystic carcinoma (ACC) who received the dose-escalation-recommended phase 2 dose (RP2D), established previously (Massard C, et al., Annals Oncol 2018, 29:1911–17). Methods Patients with advanced or metastatic cancer, measurable disease, ECOG-PS ≤1, and baseline tumor tissue were enrolled. Primary objectives were to identify a safe RP2D, confirm this dose in expansion cohorts, and document anti-tumor activity. Secondary objectives included safety and progression-free survival (PFS). The ACC expansion cohort received the RP2D regimen of 50 mg crenigacestat thrice per week in a 28-day cycle until disease progression or other discontinuation criteria were met. Results Twenty-two patients with ACC were enrolled in the expansion cohort (median age of 60 years). Median treatment duration was 3 cycles with 6 patients remaining on treatment. There were no objective responses; 1 (5%) patient had an unconfirmed partial response. Disease control rate was 73% and 4 patients had stable disease ≥6 months. Median PFS was 5.3 months (95%CI: 2.4-NE)) for the 22 patients; and 7.7 months (95%CI: 4.0-NR) and 2.4 months (95%CI: 1.1-NE) in the subgroup of patients in second-line ( n = 7) or ≥ third-line ( n = 9), respectively. Frequent treatment-related-adverse events (all grades) included diarrhea, fatigue, vomiting, decreased appetite, dry mouth, and dry skin. There were no new safety signals. Conclusion The crenigacestat RP2D regimen induced manageable toxicity and limited clinical activity, without confirmed responses, in heavily pretreated patients with ACC.

Discontinuation

Adenoid Cystic Carcinoma

10.1007/s10637-019-00739-x

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Citations (59)

A phase II trial of docetaxel and cisplatin combination in patients with locally advanced undifferentiated carcinoma of nasopharyngeal type (UCNT): Study update

Journal of Clinical Oncology (2006)

M. Yamouni Karim A. Benhadji Y. Beldjilali I. Lahfa D. Yekrou

5579 Background: The standard treatment of locally advanced undifferentiated carcinoma of nasopharyngeal type (UCNT) is cisplatin based chemotherapy followed by locoregional radiotherapy. The purpose of this study is to assess the antitumor activity and toxicity of a new neoadjuvant chemotherapy regimen combining docetaxel (D) and cisplatin (C). Patients and Methods: Previously untreated patients (pts) with histologically diagnosed locally advanced UCNT (Stages IVa and IVb TNM/UICC 1997) received D 75 mg/m 2 and C 75 mg/m 2 both on day 1, cycles were repeated every 21 days. Every pts received three cycles in a neoadjuvant setting before radiotherapy (4 to 6 weeks after the third cycle of DC). Pts were evaluated by clinical examination, CT scan of nasopharynx and nasofibroscopy with biopsy. Primary end point was tumor response. Secondary end points were disease free survival (DFS), toxicity and overall survival. Results: 75 pts were enrolled in this trial, 54 males and 21 females with a median age of 41 years (range 18–69), WHO performance status of 0–1 in 71 pts and 2 in 4 pts. 19 pts had stage IVa and 56 pts had stage IVb. Toxicity, tumor response and survival over tree years were assessable in 75 pts. After 225 cycles, grade 3 & 4 toxicity (NCI-CTC 2.0) were: neutropenia (12%), febrile neutropenia (2%), anemia (1%), nausea and vomiting (23%), diarrhea (8%), mucositis (1%), reversible alopecia (70%). Two pts had onycolysis. Response rates for the 75 pts were: complete pathologic response 37% (28 pts), partial response 52% (39 pts), stable disease 8% (6 pts) and progression 3% (2 pts). The overall response rate was 89%. 74 pts (98%) had complete response after radiotherapy and one patient had stable disease. 31 patients had recurrence: 25 locoregional, and 6 metastatic (3 with bone metastasis, 2 hepatic metastasis and 1 cerebral metastasis). DFS and overall survival at 3 years were respectively 57% and 65%. Conclusion: DC chemotherapy followed by radiation therapy is an effective regimen for the treatment of advanced UCNT. This treatment has an acceptable safety profile. These data need to be compared to concurrent chemoradiotherapy to assess the best strategy for the management of advanced UCNT. [Table: see text]

Mucositis

Regimen

10.1200/jco.2006.24.18_suppl.5579

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Citations (3)

Novel transforming growth factor beta receptor I kinase inhibitor galunisertib (LY2157299) in advanced hepatocellular carcinoma

Liver International (2019)

Sandrine Faivre Armando Santoro Robin Kate Kelley Ed Gane Charlotte Costentin

We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP).Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS).Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2).Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival.NCT01246986 at ClinicalTrials.gov.

10.1111/liv.14113

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Citations (110)

Evaluation of the Mass Balance and Metabolic Profile of Futibatinib in Healthy Participants

Clinical Pharmacology in Drug Development (2023)

Ikuo Yamamiya Allen Hunt Fumiaki Yamashita Daryl Sonnichsen Toshiharu Muto

Abstract Futibatinib, a selective, irreversible fibroblast growth factor receptor 1–4 inhibitor, was recently approved for FGFR2 rearrangement–positive cholangiocarcinoma. This Phase I study evaluated the mass balance and metabolic profile of 14 C‐futibatinib single oral 20‐mg dose in healthy participants (n = 6). Futibatinib was rapidly absorbed; median time to peak drug concentration was 1.0 hours. The mean elimination half‐life in plasma was 2.3 hours for futibatinib, and 11.9 hours for total radioactivity. Mean recovery of total radioactivity was 70% of the dose, with 64% recovered in feces and 6% in urine. The major excretion route was fecal; negligible levels were excreted as parent futibatinib. Futibatinib was the most abundant plasma component, comprising 59% of circulating radioactivity (CRA). The most abundant metabolites were cysteinylglycine‐conjugated futibatinib in plasma (13% CRA) and reduction of desmethyl futibatinib in feces (17% of dose). In human hepatocytes, 14 C‐futibatinib metabolites included glucuronide and sulfate of desmethyl futibatinib, whose formation was inhibited by 1‐aminobenzotriazole (a pan‐cytochrome P450 inhibitor), and glutathione‐ and cysteine‐conjugated futibatinib. These data indicate the primary metabolic pathways of futibatinib are O‐desmethylation and glutathione conjugation, with cytochrome P450 enzyme‐mediated desmethylation as the main oxidation pathway. 14 C‐futibatinib was well tolerated in this Phase 1 study.

Glucuronide

Desmethyl

Metabolic pathway

10.1002/cpdd.1271

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Citations (7)

136 Phase II trial of docetaxel (D) and cisplatin (C) combination in locally advanced undifferentiated carcinoma of nasopharyngeal type (UCNT)

European Journal of Cancer Supplements (2003)

M. Yamouni Y. Beldjillali I. Lahfa Karim A. Benhadji B. Larbaoui

Chronic myelogenous leukemia

Imatinib Mesylate

10.1016/s1359-6349(03)90169-8

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Citations (0)