Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer

Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9–11.4) and 8.9 (90% CI = 2.7–15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6–40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8+ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.

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A phase I/II study of ABT-888 in combination with 5-fluorouracil (5-FU) and oxaliplatin (Ox) in patients with metastatic pancreatic cancer (MPC).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.147 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 147-147 ◽

Cited By ~ 11

Author(s):

Michael J. Pishvaian ◽

Hongkun Wang ◽

Tingting Zhuang ◽

Aiwu Ruth He ◽

Jimmy J. Hwang ◽

...

Keyword(s):

Phase I ◽

Parp Inhibitor ◽

Gene Mutations ◽

Brca2 Gene ◽

Progression Free Survival ◽

Final Analysis ◽

Primary Objective ◽

Repair Mechanisms ◽

Recommended Phase Ii Dose ◽

Ecog Ps

147 Background: The PARP inhibitor, ABT-888 is a potent sensitizing agent for, and has been safely combined with DNA-damaging chemotherapies. The sensitizing effects of ABT-888 are magnified when cancer cells harbor underlying defects in DNA repair mechanisms, such as BRCA2 mutations. Methods: We have initiated a Phase I/II trial, and we present here the data from the Phase I portion. Patients (pts) with MPC who had any number of prior therapies were eligible. A standard 3+3 dose escalation of ABT-888 was employed, in cohorts of 40, 60, 80, 100, 150, 200, 250, and 300mg orally twice a day, days 1-7 of a 14 day cycle. Pts also received 85mg/m2 of Ox, 400mg/m2 of 5-FU, and 400mg/m2 of leucovorin on Day 1, and 2400mg/m2 of 5-FU continuous infusion Days 1-3. Restaging studies were performed every 4 cycles. The primary objective was to determine the Recommended Phase II Dose (RP2D) of ABT-888 combined with 5-FU and Ox. Secondary clinical objectives included an assessment of the pharmacokinetics (PKs) of ABT-888 metabolism, as well as response rate (RR), progression-free survival (PFS), and overall survival (OS). Results: Between 01-2011 and 09-2012, 22 pts received treatment. 55% were male; median age = 64, most with an ECOG PS of 1. 55% were previously untreated. The first 6 pts experienced persistent ≤Grade 2 myelosuppression, primarily thrombocytopenia, prompting an amendment to drop the 5-FU bolus. In the latter 16 pts, the combination of ABT-888 plus 5-FU and Ox was well tolerated, with no DLTs. The RP2D is expected to be 300mg BID of ABT-888, with the final analysis including ABT-888 PKs to be presented. For the 22 pts, the RR was 14%, and the PFS and OS were 2.9 and 5.4 months, respectively. Of the 11 previously untreated pts, the RR was 18%, and the PFS and OS were 4.3 and 7.7 months, respectively. 2 pts with deleterious mutations in BRCA2 were included: Pt 6 had a PR and remains on study after 17 months; Pt 14 had a CR and a normalization of CA 19-9, and is still on treatment after 10 months. Conclusions: The combination of ABT-888, 5-FU, and Ox is safe and well tolerated. The combination has demonstrated promising efficacy in MPC, particularly in pts with BRCA2 gene mutations. Clinical trial information: NCT01489865.

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Phase I study of irinotecan/5-fluorouracil/leucovorin (FOLFIRI) with sunitinib for advanced gastroesophageal cancers (EGC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15569 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15569-e15569

Author(s):

Sarbajit Mukherjee ◽

Christos Fountzilas ◽

Patrick McKay Boland ◽

Kristopher Attwood ◽

Wei Tan ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Kinase Inhibitor ◽

Objective Response ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Clinical Activity ◽

Free Survival

e15569 Background: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor with activity against VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with chemotherapy in preclinical models. We hypothesized that S+FOLFIRI combination will have increased efficacy in advanced EGC. Methods: This was a phase I study for patients with advanced chemo naïve EGC. Dose escalation used a standard 3+3 design. The primary objective was to determine the tolerability and safety of S+FOLFIRI. Secondary objectives were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-three patients participated in the study (Male 78%, Female 22%). Median age was 60 (Range: 37-77) years. Median follow up time was 67.5 (95% CI: 58.9, 76) months. The most frequently reported adverse events were neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%) and fatigue (52%; G3/4:17%).Two dose limiting toxicities (DLTs) were noted each at dose level (DL) 1 and 1A, one at DL 1B and 3 at DL 2 (Table 1). Maximum tolerated dose was determined at DL 1B. At the time of data reporting 21 patients had died. Two patients came off the study per investigator request. All patients were evaluated for efficacy. The median OS and PFS were 12.4 (95% CI: 8.9, 16.5) months and 6.2 (95% CI: 3.4, 13.5) months, respectively. Conclusions: S+FOLFIRI was reasonably tolerated, with a manageable safety profile and signs of clinical activity in patients with advanced EGC. This study was supported by a research grant from Pfizer, Inc. Clinical trial information: NCT00524186. [Table: see text]

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Randomized, phase II study of ficlatuzumab with or without cetuximab in patients with pan-refractory, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps6594 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS6594-TPS6594

Author(s):

Julie E. Bauman ◽

Denise Roe ◽

Nabil F. Saba ◽

Jessica Ruth Bauman ◽

John M. Kaczmar ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

Resistance Mechanism ◽

Progression Free Survival ◽

Primary Objective ◽

Platinum Resistance ◽

Intrinsic Resistance ◽

Eligibility Criteria ◽

Randomized Phase Ii ◽

Clinical Resistance

TPS6594 Background: Patients with pan-refractory R/M HNSCC, with clinical resistance to cytotoxic therapy, anti-EGFR molecular targeting, and immunotherapy, have poor survival. An established tumor-intrinsic resistance mechanism to cetuximab, an anti-EGFR IgG1 monoclonal antibody (mAb), is activation of the hepatocyte growth factor (HGF)/cMet pathway, which converges with the EGFR network at both the PI3K/Akt and MAPK nodes allowing for reciprocal compensation. Moreover, over-expression of HGF in the tumor microenvironment is immunosuppressive. Convergent data suggest that HGF/cMet pathway inhibition concurrent with EGFR blockade may overcome cetuximab resistance. We previously reported a Phase I study of ficlatuzumab, a humanized anti-HGF IgG1 mAb, with cetuximab in cetuximab-resistant R/M HNSCC. The combination showed promising safety, overall response rate (ORR) and progression-free survival (PFS). Preliminary biomarker analyses showed that high circulating cMet was associated with poor PFS whereas serum Veristrat, a proteomic classifier associated with worse prognosis in the setting of anti-EGFR monotherapy, was not. An increase in total peripheral T cells, particularly the CD8+ subset, was associated with treatment response while progression was associated with expansion of a unique myeloid population. We designed a follow-on randomized phase II trial evaluating ficlatuzumab with or without cetuximab in pan-refractory, R/M HNSCC with signaling and immune correlatives. Methods: This is a multicenter phase II trial with a randomized, non-comparative, two-arm design (ficlatuzumab 20 mg/kg with or without cetuximab 500 mg/m2 every 2 weeks) in patients with pan-refractory R/M HNSCC. Key eligibility criteria include: R/M HNSCC; cetuximab resistance (progression during or within 6 months of cetuximab-radiation or palliative cetuximab); platinum resistance; prior exposure to anti-PD1 mAb; ECOG 0-1; consent to baseline research biopsy. The primary objective is to evaluate the efficacy of each arm as measured by PFS. To test the hypothesis that either regimen improves historical PFS from 2 to 3.33 months requires 66 eligible patients. Key secondary endpoints are ORR and survival. Mechanistic biomarkers include tumor HGF/cMet pathway activation, tumor and peripheral immune profiles, soluble cMet, and serum Veristrat. Thirty-five of 66 subjects have enrolled at 6 centers. A Bayesian continuous monitoring rule for futility has not been triggered for either arm. Clinical trial information: NCT03422536 .

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A phase I study of ganetespib in advanced hepatocellular carcinoma (HCC).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.4_suppl.259 ◽

2013 ◽

Vol 31 (4_suppl) ◽

pp. 259-259

Author(s):

Lipika Goyal ◽

Raymond Couric Wadlow ◽

Lawrence Scott Blaszkowsky ◽

Brian M. Wolpin ◽

Eamala Vasudev ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Objective Response ◽

Study Drug ◽

Progression Free Survival ◽

Median Number ◽

Primary Objective ◽

Advanced Hepatocellular Carcinoma ◽

Dose Escalation Study ◽

Advanced Hcc

259 Background: Ganetespib is an Hsp90 inhibitor that downregulates EGFR, VEGFR, HER2, MET, IGF-IR, and other Hsp90 client proteins involved in hepatocarcinogenesis, thereby making it an attractive therapy for HCC. This multicenter Phase I study was performed to establish the safety, tolerability, recommended Phase 2 dose (RP2D), and preliminary activity of ganetespib in patients with advanced HCC. Methods: Thirteen patients with advanced HCC, Child-Pugh A or B cirrhosis, progression on or intolerance to sorafenib, and ECOG PS ≤ 1 were enrolled in a standard 3x3 dose escalation study at ganetespib doses of 100 mg/m2, 150 mg/m2, and 200 mg/m2 IV given on days 1, 8, and 15 of a 28 day cycle. RECIST 1.1 response was evaluated by CT/MRI every 8 weeks. The primary objective was to determine the RP2D, and secondary objectives included assessments of safety, toxicity, pharmacokinetics, median time to progression (TTP), median progression-free survival (PFS), median overall survival (OS), and objective response rate (ORR). Results: Twelve of the 13 patients enrolled received study drug, and enrollment is ongoing for the 200 mg/m2 cohort. Of the 12 patients: male 66%; median age 57 years; median number of prior treatments 2; Asian 33%; HCC etiology (HBV 41.7%, HCV 41.7%, hemachromatosis 8.3%, unknown 16.7%); median baseline AFP 115.3 ng/mL. Median TTP for the 10 evaluable patients was 49 days (1.6 months). No responses were seen, but 2/10 (20.0%) patients had stable disease at 8 weeks. AFP response, defined as reduction from baseline of >50% in patients with an elevated baseline AFP, was seen in 0% of patients. Most common AEs: diarrhea (100%), AST elevation (58.3%), hyperglycemia (58.3%), and fatigue (58.3%). Most common Gr 3/4 AEs: hyperglycemia (25%), anemia (16.7%), lipasemia (16.7%), and ALKP elevation (16.7%). One (8.3%) patient had a fatal AE, septic shock, within 30 days of receiving the drug. One DLT was observed: Gr 3 lipasemia at the 100mg/m2 dose. Conclusions: Ganetespib had a manageable safety profile and demonstrated limited efficacy in patients with advanced HCC. Determination of the R2PD, further assessment of clinical efficacy, and analysis of molecular markers are still pending, and a follow-up Phase II study will be considered based on this data. Clinical trial information: NCT01665937.

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Phase I study of fluzoparib, a PARP1 Inhibitor in combination with apatinib and paclitaxel in patients (pts) with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4060 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4060-4060

Author(s):

Jian-Ming Xu ◽

Rongrui Liu ◽

Yi Ba ◽

Da Jiang ◽

Mingxia Wang ◽

...

Keyword(s):

Febrile Neutropenia ◽

Phase I ◽

Phase I Study ◽

Gastroesophageal Junction ◽

Progression Free Survival ◽

Tumor Growth Inhibition ◽

Expansion Phase ◽

Grade 3 ◽

Recommended Phase Ii Dose ◽

Dose Levels

4060 Background: Fluzoparib (SHR3162) is an oral, selective PARP1 inhibitor. In our gastric cancer PDX model, fluzoparib + apatinib + paclitaxel demonstrated significant tumor growth inhibition as compared to apatinib alone, and fluzoparib + paclitaxel. In this phase I study, we hypothesized that the combination of fluzoparib+apatinib+paclitaxel should be safe and active in pts with advanced gastric and GEJ cancer. Methods: Dose-escalation phase (P1) explored 4 dose levels of fluzoparib with a 3+3 design to identify a recommended phase II dose (RP2D) for further study. Pts received fluzoparib (20, 30, 40, 60 mg/twice daily)+apatinib (250mg/day)+paclitaxel (60mg/m2, Day1, 8, 15). Dose-expansion phase (P2) was to assess safety and efficacy. Pts received RP2D of fluzoparib+apatinib+paclitaxel until progression or intolerant toxicity. Treatment was repeated every 4 weeks. Pts had to have progressive disease after standard platinum-based regimen treatment. Adverse events (AE), PK, and response per RECIST 1.1 (every 8 wks in pts with measurable disease) were assessed. Results: 39 pts (median age 58) have been treated in P1 and P2, including fluzoparib 20mg (n=4), 30mg (n=27; 6 pts in P1, 21 pts in P2), 40mg (n=6), and 60mg (n=2). The median treatment duration for this study was 2.8 months. No DLTs were reported in 20mg cohort. One DLT occurred in 30 mg cohort (grade 3 [G3] hypophosphatemia), 1 DLTs (1 grade 4 [G4] febrile neutropenia) occurred and 1 G4 neutropenia occurred and recovered in 3 days in 40mg cohort, 2 DLTs (1 G4 neutropenia, 1 G4 febrile neutropenia) in 60mg cohort. Therefore, 40 mg dose was deemed the MTD. There were no treatment-related deaths on study. The most common AEs≥G3 were neutropenia, febrile neutropenia, and hypertension. 1 treatment-related discontinuation was observed. Of 36 evaluable pts, 12 (30.0%) had confirmed partial response and 13 had stable disease (36.1%). Median progression-free survival was 4.9 months. PK analysis will be presented. Conclusions: The RP2D of combination of fluzoparib + apatinib + paclitaxel is well tolerated and has activity in pts with advanced gastric and EGJ cancer who have failed to platinum-based regimen. Clinical trial information: NCT 03026881.

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Phase I Study of the Combination of Carfilzomib and Panobinostat for Patients with Relapsed and Refractory Myeloma: A Multiple Myeloma Research Consortium (MMRC) Clinical Trial

Blood ◽

10.1182/blood.v124.21.32.32 ◽

2014 ◽

Vol 124 (21) ◽

pp. 32-32 ◽

Cited By ~ 10

Author(s):

Jonathan L. Kaufman ◽

Todd Zimmerman ◽

Cara A Rosenbaum ◽

Ajay K. Nooka ◽

Leonard T Heffner ◽

...

Keyword(s):

Phase I ◽

Research Funding ◽

Phase I Study ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Primary Objective ◽

Significant Activity ◽

Free Survival ◽

Common Grade ◽

Grade 3

Abstract Introduction: Patients with myeloma ultimately become refractory to current therapies, requiring new approaches to treatment. Carfilzomib is a second generation proteasome inhibitor that has demonstrated significant activity in patients with relapsed and refractory disease. Panobinostat is a pan-deacetylase inhibitor that has been shown to be effective and overcome resistance in combination with bortezomib in refractory patients. In addition, patients treated with a combination of bortezomib/dexamethasone/panobinostat had a significant improvement in progression free survival (PFS) compared to bortezomib/dexamethasone alone. Based on preclinical data supporting combined HDAC and proteasome inhibition, we hypothesized that carfilzomib and panobinostat would be safe and effective in relapsed/refractory myeloma patients. Herein we report the initial findings of the MMRC multicenter phase I study of the combination. Methods: The primary objective is to determine the maximum tolerated dose (MTD) of the combination of panobinostat and carfilzomib using a standard 3+3 alternate dose escalation design with 4 cohorts. An additional 12 patient expansion group will be treated at the MTD to further assess the activity and safety of the combination. Secondary objectives are to evaluate the extended safety of this combination and to assess response, response duration and progression free survival (PFS). Panobinostat is administered orally three times weekly for three of four weeks, ranging from 15 to 20 mg. Carfilzomib is administered IV days 1, 2, 8, 9, 15, and 16, ranging from 20/27 mg/m2 to 20/45mg/m2. Cycles are repeated every 4 weeks. Dose limiting toxicities (DLT) are determined in the first cycle, and all adverse events are assessed according to CTCAE V4. Responses are assessed using IMWG criteria (plus MRs as per the EBMT criteria). Results: To date, 20 patients in four cohorts have been enrolled and all have completed the first cycle. Median age is 64.5 years (48-75). All patients had refractory and progressive disease; with a median number of 4) prior treatment lines. Three DLTs occurred. One patient had grade 4 thrombocytopenia with grade 3 acute kidney injury, one patient developed persistent grade 4 thrombocytopenia without bleeding and one patient had grade 3 diarrhea uncontrolled by maximal medical therapy. The MTD is panobinostat 20 mg and carfilzomib 20/36 mg/m2. The most common grade 3 toxicities were hematologic. Regardless of causality, grade 3 or higher anemia, thrombocytopenia and neutropenia occurred in 35%, 35%, and 20% of patients, respectively. The most common grade 3/4 or higher nonhematologic toxicities were fatigue (15%), anorexia (10%), hyponatremia (10%) and nausea (10%). The overall response rate is 50% with 30% PRs and 20% VGPR or better. The median PFS is 14.3 months. Conclusion: The combination of carfilzomib and panobinostat is well tolerated with no unexpected toxicities. Response, durability of response, and PFS are encouraging and warrant further study. Disclosures Kaufman: Millennium: The Takeda Oncology Co.: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Off Label Use: Carfilzomib treatment in amyloidosis . Zimmerman:Onyx: Honoraria. Heffner:Amgen: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Dana Farber CI: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Idera: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Spectrum: Honoraria, Research Funding; Talon Therapeutics: Honoraria, Research Funding. Harvey:Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Research Funding; Celgene: Research Funding; Acetylon: Research Funding; Amgen: Research Funding. Gleason:Celgene: Consultancy; Novartis: Consultancy. Lewis:Array BioPharma: Consultancy. Lonial:Millennium: The Takeda Oncology Company: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

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Phase I study of H3B-6527 in hepatocellular carcinoma (HCC) or intrahepatic cholangiocarcinoma (ICC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.4090 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 4090-4090

Author(s):

Teresa Macarulla ◽

Victor Moreno ◽

Li-Tzong Chen ◽

Michael B. Sawyer ◽

Lipika Goyal ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Progression Free Survival ◽

Therapeutic Benefit ◽

Clinical Activity ◽

Drug Discontinuation ◽

Prior Therapy ◽

Heavily Pretreated ◽

Recommended Phase Ii Dose ◽

Ecog Ps

4090 Background: Evidence suggests that hyperactivated fibroblast growth factor 4 (FGFR4) signaling pathway leads to enhanced tumor growth. Targeting FGFR4 may have therapeutic benefit in tumors with altered FGF19 signaling. A phase I study (NCT02834780) was undertaken to assess H3B-6527, a highly selective covalent FGFR4 inhibitor, in patients with HCC/ICC. Methods: Adults with advanced HCC/ICC, ECOG PS 0-1, well compensated liver function, who progressed after > one prior therapy, received H3B-6527 po daily (QD) or twice-daily (bid) on a 21-day cycle following a 3+3 design. Doses ranged from 300-2000mg QD or 500-700mg BID. Patients in dose escalation were treated regardless of FGF19 status. Patients in expansion had FGF19+ tumors by mRNA testing. Adverse events (AEs), and pharmacokinetics (PK) were assessed. Response was determined by RECIST 1.1/mRECIST imaging every 6 weeks. Results: Study enrollment is complete at 128 patients. Ninety HCC patients were treated (QD = 48, bid = 42). ICC enrollment was suspended after 38 patients due to limited efficacy. No dose-limiting toxicities were seen and no grade 4-5 treatment related AEs have been observed. Recommended Phase II dose for H3B-6527 is 1000mg QD based upon safety, efficacy, and PK data. Grade 3 TEAEs have occurred in 12.5% of patients on QD dosing. Treatment related TEAEs were seen in 62.5% of patients on the QD schedule, with diarrhea (45.8%), fatigue (12.5%), and nausea (12.5%) most frequent. Drug discontinuation due to AEs for QD dosing was 8.3%. Interim data analysis shows that, for HCC patients with >2 prior lines of therapy treated on QD schedule, overall survival was 10.6m, progression-free survival 4.1m, overall response rate 16.7% (all partial responses), and clinical benefit rate 45.8% (responders + durable stable disease >17 weeks). H3B-6527 Cmax and AUC were lower at 300 mg dose but then similar across 500–2000 mg doses. Following oral administration of 1000 mg fasted, H3B-6527 plasma concentration reached peak at a Tmax of ̃2-3 hours and then decayed exponentially, with terminal half-life of ̃4-5 hours. There was no accumulation following QD dose. Dosing with food did not meaningfully change H3B-6527 plasma exposure. Conclusions: H3B-6527 was well tolerated and demonstrated a favorable toxicity and safety profile and encouraging clinical activity in heavily pretreated HCC patients. Final trial results will be presented at conference. Clinical trial information: NCT02834780.

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Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study

Scientific Reports ◽

10.1038/s41598-021-02527-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kuo-Chen Wei ◽

Peng-Wei Hsu ◽

Hong-Chieh Tsai ◽

Ya-Jui Lin ◽

Ko-Ting Chen ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

Progression Free Survival ◽

Multicenter Trial ◽

Newly Diagnosed ◽

Open Label ◽

Free Survival ◽

Asian Patients ◽

Newly Diagnosed Glioblastoma ◽

Secondary Endpoints

AbstractAsunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.

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