First in Human Study of IBI308 in Chinese Subjects With Advanced Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, tolerability and efficacy of IBI308 monotherapy or in combination with chemotherapy in patients with certain types of advanced solid tumors. Another purpose is to determine the pharmacokinetics, pharmacodynamics and immunogenicity of IBI308.

Detailed Description
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This is a study which consists of phase 1a study (dose escalation stage) and phase 1b study (expansion stage). Phase 1a study will adopt the classical 3+3 dose escalation design, exploring safety and tolerance of 4 dose cohorts (1mg/kg, 3mg/kg, 200mg and 10mg/kg) and determining the recommended dose for phase 1b study. Phase 1b is expansion study of 8 cohorts which will evaluate anti-tumor efficacy and safety of eight IBI308 monotherapy or in combination with chemotherapy. Cohort A is IBI308 monotherapy for advanced melanoma. Cohort B is IBI308 monotherapy for advanced digestive system carcinoma or neuroendocrine neoplasm after failure or intolerance of first line standard therapy. Cohort C is IBI308 monotherapy for advanced non-small cell lung cancer (NSCLC) after failure or intolerance of first line standard therapy. Cohort D is IBI308 in combination with cisplatin and pemetrexed for treatment naïve locally advanced, recurrent or metastatic non-squamous NSCLC. Cohort E is IBI308 in combination with gemcitabine and cisplatin for treatment-naïve locally advanced, recurrent or metastatic squamous NSCLC. Cohort F is IBI308 in combination with oxaliplatin and capecitabine for treatment naïve locally advanced gastric or gastroesophageal junction adenocarcinoma. Cohort G is IBI308 in combination with etoposide and cisplatin for treatment naïve locally advanced, recurrent or metastatic high grade(G3) neuroendocrine tumor. Cohort H is IBI308 in combination with irinotecan and 5-FU for advanced high grade(G3) neuroendocrine tumor after failure of first line standard therapy. Phase 1a and 1b consist of screening period (28 days before enrollment), treatment period and follow up period (every 3 months until death or the end of study). In phase 1a, dose limiting toxicity (DLT) will be recorded for up to 28 days after the 1st dose of IBI308. Efficacy will be evaluated by RECIST v1.1. Adverse events will be monitored throughout the study. Further exploration of pharmacokinetic/pharmacodynamics and immunogenicity information will be assessed throughout the trial.

Official Title
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An Open-Label, Multicenter Study of IBI308 in Subjects With Selected Advanced Solid Tumors

Conditions
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Cancer, Solid Tumor

Intervention / Treatment
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* Drug: IBI308
* Drug: IBI308\Cisplatinum\Pemetrexed
* Drug: IBI308\cisplatin\gemcitabine
* Drug: IBI308\oxaliplatin\capecitabine
* Drug: IBI308\etoposide\cisplatin
* Drug: IBI308\irinotecan\5-FU


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status grade 0 or 1 Adequate bone marrow, liver, and renal function defined as: 1) Absolute neutrophil count >= 1.5* 10^9 cells/litre (L); 2) Platelets >=100 x 10^9 cells/L; 3) Hemoglobin >= 9 gram/deciliter (g/dL); 4) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <= 2.5 * upper limit of normal (ULN) for participants without hepatic cell cancer and hepatic metastasis, ALT and AST <= 5 * ULN for participants with hepatic cell cancer or hepatic metastasis; 5) Total bilirubin (TBIL) < 1.5 * ULN for participants without hepatic cell cancer, hepatic metastasis and confirmed/suspicious Gilbert syndrome, TBIL < 3 * ULN for participants with hepatic cell cancer, hepatic metastasis or confirmed/suspicious Gilbert syndrome; 6) Creatinine determined by serum creatinine levels <=1.5 * ULN or a calculated creatinine clearance of >= 50 mL/min/1.73 m^2; 7) urine protein - +, 24 hour urine < 1 gram for participants with urine protein ++ or above; 8) activated partial thromboplastin time and international normalized ratio <= 1.5 * ULN; 9) thyroid stimulating hormone and free thyroxine 4 within normal range Tumor type Phase 1a: advanced solid tumors after failure of standard therapy Phase 1b Cohort A: cytologically or histologically confirmed advanced melanoma Phase 1b Cohort B: cytologically or histologically confirmed advanced malignancies of the digestive system after failure of at least 1 line of standard therapy Phase 1b Cohort C: cytologically or histologically confirmed advanced NSCLC without known epithelial growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement after failure of 1st line standard therapy Phase 1b Cohort D: treatment naive cytologically or histologically confirmed inoperable locally advanced (stage IIIB) or advanced (stage IV) nsNSCLC without known EGFR mutation and ALK rearrangement, participants with disease recurrence or progression within 6 months after completion of prior platinum doublet-based chemotherapy regimen as neoadjuvant or adjuvant therapy are not eligible Phase 1b Cohort E: Cytologically or histologically confirmed, treatment naïve locally advanced, recurrent or metastatic squamous NSCLC without known EGFR mutation and ALK rearrangement. Participants with Stage IIIB NSCLC who progressed within 6 months after completion of platinum-based chemotherapy are not eligible. Phase 1b Cohort F: Histologically confirmed locally advanced, recurrent or metastatic gastric or esophagogastric junction adenocarcinoma without known HER2 amplification. Phase 1b Cohort G: Cytologically or histologically confirmed, treatment naïve locally advanced, recurrent or metastatic high grade(G3) neuroendocrine tumor with Ki-67>20%. Phase 1b Cohort H: Cytologically or histologically confirmed advanced high grade(G3) neuroendocrine tumor with Ki-67>20% after failure of first line standard therapy. Participants progressed within 6 months after completion of adjuvant or neoadjuvant chemotherapy are eligible. At least 1 measurable site of disease per RECIST v1.1 Exclusion Criteria: Prior treatment of any antibody of PD-1 or PD-L1 Prior treatment of ipilimumab, unless all the following requirements are met: Full resolution of ipilimumab related adverse effects (including immune related adverse effects) and no treatment for these adverse events (AEs) for at least 4 weeks prior to the time of enrollment Minimum of 12 weeks from the first dose of ipilimumab and >6 weeks from the last dose No history of severe immune related adverse effects from ipilimumab (CTCAE Grade 4; CTCAE Grade 3 requiring treatment >4 weeks) Unequivocal PD following a dose of ipilimumab HIV infection Active HBV or HCV infection Uncontrolled complication including but not limited to : Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias or congestive heart failure History of stroke, myocardial infarction or intracranial hemorrhage within 6 months prior to the enrolment History or risk of autoimmune disease Known interstitial lung disease

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a<br>Participants will receive IBI308 1mg/kg, 3mg/kg or 10mg/kg intravenous every 2 weeks, or 200mg intravenous every 3 weeks and will be continued until disease progression or unacceptable toxicity. Drug: IBI308 | Drug: IBI308<br> <br> |
| Experimental: Phase 1b Cohort A<br>Participants will receive IBI308 200mg intravenous every 3 weeks and will be continued until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment. Drug: IBI308 | Drug: IBI308<br> <br> |
| Experimental: Phase 1b Cohort B<br>Participants will receive IBI308 200mg intravenous every 3 weeks and will be continued until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment. Drug: IBI308 | Drug: IBI308<br> <br> |
| Experimental: Phase 1b Cohort C<br>Participants will receive IBI308 200mg intravenous every 3 weeks and will be continued until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment. Drug: IBI308 | Drug: IBI308<br> <br> |
| Experimental: Phase 1b Cohort D<br>Participants will receive IBI308 200mg in combination with cisplatin 75mg/m2 and pemetrexed 500mg/m2 intravenously every 3 weeks for upto 4 cycles, and those who haven't progressed will receive maintenance treatment of IBI308 200mg in combination with pemetrexed 500mg/m2 intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment. Drug: IBI308/Cisplatinum/Pemetrexed | Drug: IBI308\Cisplatinum\Pemetrexed<br> <br> |
| Experimental: Phase 1b Cohort E<br>Participants will receive IBI308 200mg and cisplatin 75mg/m2 intravenously every 3 weeks in combination with gemcitabine 1250mg/m2 intravenously day 1 and 8 of every 3 weeks for upto 6 cycles, and those those who haven't progressed will receive maintenance treatment of IBI308 200mg intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment. Drug: IBI308\gemcitabine\cisplatin | Drug: IBI308\cisplatin\gemcitabine<br> <br> |
| Experimental: Phase 1b Cohort F<br>Participants will receive IBI308 200mg and oxaliplatin 130mg/m2 intravenously every 3 weeks in combination with capecitabine 1000mg/m2 orally day 1 to 14 of every 3 weeks for upto 6 cycles, and those those who haven't progressed will receive maintenance treatment of IBI308 200mg intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment. Drug: IBI308\oxaliplatin\capecitabine | Drug: IBI308\oxaliplatin\capecitabine<br> <br> |
| Experimental: Phase 1b Cohort G<br>Participants will receive IBI308 200mg in combination with cisplatin 75mg/m2 intravenously and etoposide 100mg/m2 intravenously day 1 to 3 of every 3 weeks for upto 6 cycles. Those who haven't progressed will receive maintenance treatment of IBI308 200mg intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment. Drug: IBI308\etoposide\cisplatin | Drug: IBI308\etoposide\cisplatin<br> <br> |
| Experimental: Phase 1b Cohort H<br>Participants will receive IBI308 200mg in combination with irinotecan 125mg/m2 intravenously day 1and 8 and 5-FU 1000mg/m2 intravenously day 1 to 3 of every 3 weeks for upto 6 cycles.Those who haven't progressed will receive maintenance treatment of IBI308 200mg intravenously every 3 weeks until disease progression or unacceptable toxicity or withdrawal of informed consent or up to 24 months of treatment. Drug: IBI308\irinotecan\5-FU | Drug: IBI308\irinotecan\5-FU<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing Dose-limiting Toxicities (DLTs) |  | Up to 28 days in Cycle 1 | 
| Number of All Study Participants Who Demonstrate a Tumor Response |  | Through out the study (up to 2 years) | 
| Objective Response Rate (ORR) According to RECIST 1.1 as Assessed by Independent Review Committee by Investigator | ORR was defined as the percentage of participants in the analysis population who had achieved BOR of CR or PR according to RECIST 1.1. | Through out the study (up to 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PFS According to RECIST 1.1 as Assessed by Investigator |  | Through out the study (up to 2 years) | 
| DOR According to RECIST 1.1 as Assessed by Investigator |  | Through out the study (up to 2 years) | 
| TTR According to RECIST 1.1 as Assessed by Investigator |  | Through out the study (up to 2 years) | 
| OS for Participants |  | Through out the study | 
| Area Under the Concentration-time Curve From Zero Time (Predose) to the Time of the Last Measurable Concentration (AUC0-t) |  | Cycle 1: pre-dose, post-dose at 0, 1, and 6 hours, and Days 2, 3, 8, 15, and 22, and 29 | 
| Maximum Concentration (Cmax) of Sintilimab in Solid Tumor Participants |  | Cycle 1: pre-dose, post-dose at 0, 1, 6 hours, and Days 2, 3, 8, 15, and 22, and 29 | 
| Time to Maximum Concentration (Tmax) of Sintilimab in Solid Tumor Participants |  | Cycle 1: pre-dose, post-dose at 0, 1, 6 hours, and Days 2, 3, 8, 15, and 22, and 29 | 
| The Half-life (t1/2) of IBI308 in Plasma After Single Dose Administration |  | Cycle 1: pre-dose, post-dose at 0, 1, 6 hours, and Days 2, 3, 8, 15, and 22, and 29 | 
| Volume of Distribution of IBI308 in Plasma After Single Dose Administration |  | Cycle 1: pre-dose, post-dose at 0, 1, 6 hours, and Days 2, 3, 8, 15, and 22, and 29 | 
| Clearance of IBI308 in Plasma After Single Dose Administration |  | Cycle 1: pre-dose, post-dose at 0, 1, 6 hours, and Days 2, 3, 8, 15, and 22, and 29 |