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Gemcitabine

Erlotinib Hydrochloride

3mg/kg IV, 10mg/kg IV, 15mg/kg IV, 25mg/kg, 35mg/kg IV, 45mg/kg IV - Biweekly, 35/17.5mg/kg, 45/22.5 mg/kg - Weekly

FG-3019

Albert C Koong, MD, PhD

J. Marc Pipas, MD

Vincent J Picozzi, MD, PhD

Peter J O'Dwyer, MD

Smitha Krishnamurthi, MD

Charles Lopez, MD

Nathan Bahary, MD

Objectives

* Primary: To evaluate the safety and tolerability of FG-3019 in combination with gemcitabine and erlotinib
* Secondary: To evaluate the efficacy and pharmacokinetics of FG-3019 in combination with gemcitabine and erlotinib

A Phase 1 Study of Safety and Bioactivity With FG-3019 in Combination With Gemcitabine and Erlotinib for Subjects With Locally Advanced or Metastatic Pancreatic Cancer

FibroGen

Participants received 30 milligrams per meter square (mg/m\^2) of S-1 orally twice daily (BID) for 2 weeks (i.e., Day 1 to 14), followed by 1 week recovery period (i.e., Day 15 to 21; one cycle equaled 21 days), treatment was repeated every 3 weeks until death, progression of disease, occurrence of intolerable side effects, withdrawal of consent, or removal by Investigator, whichever comes first.

All participants received S-1 orally at a dose of 30 mg/m2 BID for 14 days followed by a 1-week recovery period, repeated every 3 weeks. The trial was planned to proceed to the second stage only if sufficient efficacy was demonstrated in Stage 1.

Taiho Central

The purpose of this study is to determine whether S-1 is effective in slowing tumor activity in participants with locally advanced or metastatic pancreatic cancer who have not had chemotherapy. The study is also looking at the safety of S-1.

Locally advanced or metastatic pancreatic cancer is relatively unresponsive to chemotherapy. This is true for the nucleoside analogue gemcitabine, with a response rate of approximately 10%, as well as for 5-fluorouracil (5-FU). Even when gemcitabine is combined with other chemotherapeutic drugs or biological agents, the overall tumor response rate remains basically unchanged. S-1 is a new generation oral fluoropyrimidine that combines Tegafur (5-fluoro-1-(tetrahydro-2-furanyl)-2,4(1H,3H)-pyrimidinedione \[FT\]), an oral prodrug of 5-FU, with two modulators, Gimeracil (5-chloro-2,4-dihydroxypyridine \[CDHP\]), which inhibits 5-FU degradation by dihydropyrimidine dehydrogenase (DPD) inhibition, and Oteracil potassium (Oxo), which inhibits 5-FU phosphorylation in the digestive tract. This combination of 3 compounds is designed to achieve enhanced antitumor activity while decreasing gastrointestinal toxicity.

Phase 2 Study of S-1 in Advanced or Metastatic Pancreatic Cancer

An Open-Label, Non-Randomized, Multicenter, Two-Stage, Phase 2 Study of S-1 in Chemotherapy-Naïve Patients With Locally Advanced or Metastatic Pancreatic Cancer

ORR was defined as the percentage of participants with objective evidence of partial response (PR) or complete response (CR) and was based on the best overall response across all cycles for each participant. Tumor response was assessed according to the Response Evaluation Criteria In Solid Tumors (RECIST). For target lesions response, CR was defined as the disappearance of all target lesions for at least 3 weeks and PR was defined as at least a 30% reduction in the sum of the longest diameters of the target lesions, taking as a reference the baseline sum of the longest diameters for at least 6 weeks. For non-target lesions, CR was defined the disappearance of all non-target lesions and normalization of tumor marker level for at least 6 weeks.

DCR was defined as the percentage of participants with objective evidence of CR, PR or stable disease (SD) determined according to RECIST. For target lesions, stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) taking as a reference the smallest sum of the longest diameters since the treatment started for at least 6 weeks. For non-target lesions, stable disease was defined a persistence of greater than or equal to (\>=) 1 non-target lesions and/or maintenance of tumor marker level above the normal limits for at least 6 weeks.

DR was calculated as date of first progressive disease (PD) or death, date after the first response of CR or PR minus date of first CR or PR plus 1. Participants who did not die and were without progressive disease were censored at last evaluable tumor response assessment. Analysis was performed by Kaplan-Meier method.

TTP was calculated as date of first PD minus date of first dose of study medication plus 1. Participants without progressive disease were censored at last evaluable tumor response assessment. Analysis was performed by Kaplan-Meier method.

OS was calculated as date of death minus date of first dose of study medication plus 1. In the absence of death confirmation, OS was censored at the date of last study follow-up. Analysis was performed by Kaplan-Meier method.

PFS was defined as date of first PD or date of death minus date of first dose of study medication plus 1. Participants who did not die and were without PD were censored at their last evaluable tumor response assessment. Analysis was performed by Kaplan-Meier method.

KPS classified participant's as per their functional impairment. The KPS ranged from 0percent (%) to 100%, (100= no signs of disease, 90% = few symptoms or signs of disease, 80%=some symptoms or signs, 70% = not capable of normal activity or work, 60% = can take care of most personal requirements, 50% = requires frequent medical care, 40% = disabled, 30% = severely disabled, hospital admission indicated but no risk of death, 20% = very ill, requires supportive measures or treatment, 10% = moribund, rapidly progressive fatal disease processes, and 0% = death), where higher values represented better outcomes. Participants with baseline KPS \>=70% were included in study. Final assessment was the participant's last assessment. Participants with available data were only presented in the below data table.

Pain intensity was graded from 0 (least possible pain) to 100 (worst possible pain) on a visual analog scale (VAS). The higher score on VAS scale indicated more pain. Final assessment was the last assessment of participant's.

An AE was defined as any untoward medical event in a participants administered any dose of a study medication which may or may not have a causal relationship with the use of the study medication. An SAE was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event.

Quintiles, Inc.

United BioSource, LLC

Taiho Oncology, Inc.

Analysis was performed on safety population that included all the participants who had received at least one dose of study medication.

Participants received 30 mg/m\^2 of S-1 orally BID for 2 weeks (i.e., Day 1 to 14), followed by 1 week recovery period (i.e., Day 15 to 21; one cycle equaled 21 days), treatment was repeated every 3 weeks until death, progression of disease, occurrence of intolerable side effects, withdrawal of consent, or removal by Investigator, whichever comes first.

S-1 30 mg/m^2

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Safety population included all participants who had received at least one dose of study treatment.

Since the pre-defined tumor response futility criteria was not exceeded in Stage 1, participant enrollment for Stage 2 was not conducted, as pre-planned in the protocol.

Independent Assessment

Investigator Assessment

Primary efficacy population included all participants in the safety population who met the key eligibility criteria (1st line therapy in participants with measurable pancreatic locally advanced or metastatic disease) and had at least one response assessment after starting study treatment. Here, 'Number analyzed' signifies number of participants in the specified population.

Overall Tumor Response Rate (ORR)

Analysis was performed on primary efficacy population. Here, 'Number analyzed' signifies number of participants in the specified population.

Disease Control Rate (DCR)

Analysis was performed on primary efficacy population. Here, 'Number analyzed' signifies number of participants evaluable in specified category.

Duration of Response (DR)

Analysis was performed on primary efficacy population. Here, 'Number analyzed' signifies number of participants evaluable for this outcome measure.

Time to Tumor Progression (TTP)

Overall Survival (OS)

Progression-free Survival (PFS)

Baseline score 100% shift to Final assessment score 100%

Baseline score 100% shift to Final assessment score 90%

Baseline score 100% shift to Final assessment score 70%

Baseline score 100% shift to Final assessment score 0%

Baseline score 90% shift to Final assessment score 90%

Baseline score 90% shift to Final assessment score 80%

Baseline score 90% shift to Final assessment score 70%

Baseline score 90% shift to Final assessment score 60%

Baseline score 90% shift to Final assessment score 0%

Baseline score 80% shift to Final assessment score 80%

Baseline score 80% shift to Final assessment score 0%

Baseline score 70% shift to Final assessment score 0%

Number of Participants With Karnofsky Performance Status (KPS) Score - Shift From Baseline Score to Final Assessment Score

Change From Baseline in Pain Intensity

At Least 1 AE

At Least 1 SAE

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAE)

Overall Study

Micronutrients

Hematinics

Vitamins

Irinotecan

Leucovorin

Fluorouracil

Oxaliplatin

Levoleucovorin

Antimetabolites

Topoisomerase I Inhibitors

Enzyme Inhibitors

Antidotes

Protective Agents

Folic Acid

Vitamin B Complex

Trace Elements

Folinic Acid

Folate

Vitamin B9

800 mg/m2 gemcitabine at a fixed rate of 10 mg/m2/min followed by a 2-hour intravenous infusion of oxaliplatin on day 1 plus twice daily oral S-1 80-120 mg/day (based on BSA) and oral leucovorin 30 mg twice a day on day 1 to day 7, every 14 days as a cycle

oxaliplatin at a dose of 85 mg/m2, given as a 2-hour infusion, with the addition, after 30 minutes, of irinotecan at a dose of 150 mg/m2, given as a 90-minute infusion. The treatment was immediately followed by a continuous intravenous infusion via central venous catheter of leucovorin 400 mg/m2 given as a 2-hour infusion and 5-FU 2400 mg/m2 over a 46-hour period on day 1 every 14 days/cycle.

Intervention is administered to patients in this Arm.

Leucovorin(oral )

5-FU

Leucovorin(IV)

Chen Li-Tzong

A Phase II Randomized Study.Primary objective:to investigate the 6-month progression-free survival (PFS) rate i patients receiving SLOG or mFLFIRINOX as a first-line treatment for locally advanced and metastatic pancreatic cancer.

A total of 130 patients (65patients in each arm) will be calculated, based on the assumption of a 6-month PFS rate of 45% with mFOLFIRINOX vs 60% wuth SLOG, to achieve 75% power, with a drop-out rate of 10%. Two-sided test was performed with type I error=0.10.

SLOG vs mFOLFIRINOX as the First-line Treatment in Locally Advanced Uncresectable or Metastatic Pancreatic Cancer

A Phase II Randomized Study of SLOG vs mFOLFIRINOX as the First-line Treatment in Locally Advanced Uncresectable or Metastatic Pancreatic Cancer

The 6-month PFS rates of the two arms are assumed to be 60% (SLOG) vs. 45% (mFOLFIRINOX)

National Taiwan University Hospital

Taipei Veterans General Hospital, Taiwan

China Medical University Hospital

National Cheng-Kung University Hospital

Kaohsiung Medical University

Taipei Medical University Shuang Ho Hospital

Chang Gung Memorial Hospital

Tri-Service General Hospital

E-DA Hospital

National Health Research Institutes, Taiwan

BEY1107 monotherapy, 4 Cohorts, 4 weeks (administered on a 3-week-on and 1-week-off)

BEY1107 in combination with Gemcitabine, 3 Cohorts, 4 weeks (administered on a 3-week-on and 1-week-off)

BEY1107 in combination with Gemcitabine, 6 Cycles / 24 weeks (administered on a 3-week-on and 1-week-off)

Take orally with water once a day on a 3-weeks-on (21 days) continuously and 1-week-off (7 days) schedule.

BEY1107

Administer 1,000 mg/m2 of Gemcitabine intravenously for 30 minutes on Day 1, 8, 15 and 1-week-off (7days) schedule.

BeyondBio Inc.

This study is a single center, open-label, non-comparative, phase I/II clinical trial to assess the maximum tolerated dose (MTD), safety and efficacy of BEY1107 in monotherapy and in combination with gemcitabine in patient With locally advanced or metastatic pancreatic cancer.

The key purpose of the main part of the study is to assess the MTD, safety and efficacy of BEY1107 as monotherapy and combination therapy for locally advanced and/or metastatic pancreatic cancer. The main purpose of the safety lead-in (dose-finding) part of the study is to determine the safety and tolerability of BEY1107, to determine the MTD.

Patient will receive BEY1107 for 4 weeks in monotherapy for each cohort (administered in a 3-weeks-on / 1-week-off) during Phase I-1 trial.

At next stage, patient will receive BEY1107 with gemcitabine for 4weeks in phase I-2 trial.

Final stage, patient will receive BEY1107 with gemcitabine for 24weeks in phase II trial.

Blood samples will be collected for safety, pharmacokinetic and biomarker analysis. Archival of fresh biopsy tissue will also be collected for biomarker analysis.

Evaluation of Safety and Efficacy in BEY1107 in Monotherapy Gemcitabine Combination in Patient With Pancreatic Cancer

A Single Center, Open-label, Non-comparative, Phase I/II Clinical Trial to Assess the MTD, Safety and Efficacy of BEY1107 in Monotherapy and in Combination With Gemcitabine in Patient With Locally Advanced or Metastatic Pancreatic Cancer

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase 1 Study of Safety and Bioactivity With FG-3019 in Combination With Gemcitabine and Erlotinib for Subjects With Locally Advanced or Metastatic Pancreatic Cancer	NCT01181245	Locally Advance...	FG-3019	18 Years -	FibroGen
Phase 2 Study of S-1 in Advanced or Metastatic Pancreatic Cancer	NCT00651742	Locally Advance...	S-1	18 Years -	Taiho Oncology, Inc.
Phase 2 Study of S-1 in Advanced or Metastatic Pancreatic Cancer	NCT00651742	Locally Advance...	S-1	18 Years -	Taiho Oncology, Inc.
SLOG vs mFOLFIRINOX as the First-line Treatment in Locally Advanced Uncresectable or Metastatic Pancreatic Cancer	NCT03443492	Locally Advance...	S-1 Leucovorin(oral... Gemcitabine Oxaliplatin Irinotecan 5-FU Leucovorin(IV)	20 Years - 80 Years	National Health Research Institutes, Taiwan
Evaluation of Safety and Efficacy in BEY1107 in Monotherapy Gemcitabine Combination in Patient With Pancreatic Cancer	NCT03579836	Locally Advance...	BEY1107 Gemcitabine	20 Years - 80 Years	BeyondBio Inc.
SLOG vs mFOLFIRINOX as the First-line Treatment in Locally Advanced Uncresectable or Metastatic Pancreatic Cancer	NCT03443492	Locally Advance...	S-1 Leucovorin(oral... Gemcitabine Oxaliplatin Irinotecan 5-FU Leucovorin(IV)	20 Years - 80 Years	National Health Research Institutes, Taiwan
Evaluation of Safety and Efficacy in BEY1107 in Monotherapy Gemcitabine Combination in Patient With Pancreatic Cancer	NCT03579836	Locally Advance...	BEY1107 Gemcitabine	20 Years - 80 Years	BeyondBio Inc.

Spots Global Cancer Trial Database for locally advanced or metastatic pancreatic cancer