JS001 Combined With Regorafenib in Patients With Advanced Colorectal Cancer

NCT03946917 | Unknown Phase 1

• 1 other identifier: JS001/Regorafenib in mCRC
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 1

Brief Summary

Colorectal cancer is one of the most common malignancies in China. Regorafenib is the standard multi-kinase inhibitor for refractory advanced colorectal cancer. In mice, regorafenib combined with anti-PD-1 was shown superior to regorafenib, which has not yet been verified in humans. JS001 is the Chinese anti-PD-1 monoclonal antibody for injection which has been approved for melanoma. This study is the first multi-center, open-label, phase I/II clinical trial to evaluate tolerability, safety and efficacy of JS001 in combination with regorafenib tablet in patients with MSS/MSI-L/pMMR, relapsed or metastatic colorectal cancer who have failed or can not tolerate fluorouracil, oxaliplatin and irinotecan based systemic treatment. The phase I clinical trial is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of regorafenib tablet in this regimen, and select an acceptable safe dose for the phase II clinical trial to further determine safety and efficacy of this combination regimen in patients with metastatic colorectal cancer.

Conditions

Colorectal Cancer

Keywords

Regorafenib; JS001; Colorectal cancer; Microsatellite stability

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose (MTD)

  The maximum dose that patients enrolled can tolerate during dose escalation of phase I clinical trial according to mTPI method

  28 days after the first dose of JS001 and Regorafenib, assessed up to 8 months

• Dose limiting toxicity (DLT)

  Severe toxicity that may be related to JS001 or regorafenib during dose escalation of phase I clinical trial according to mTPI method

  28 days after the first dose of JS001 and Regorafenib, assessed up to 8 months

• Objective response rate (ORR)

  The ratio of patients who are evaluated as CR or PR

  from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

Secondary Outcomes (7)

• Progression free survival (PFS)

  from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

• Overall survival (OS)

  from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

• Disease control rate (DCR)

  from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

• Duration of response (DOR)

  the first assessment of a tumor as PR or CR and the first assessment as PD or any cause of death or the last follow-up date, assessed up to 2 years.

• Severe toxicity

  from the initiation date of first cycle to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years

Study Arms (1)

JS001/regorafenib

EXPERIMENTAL

recombinant humanized anti-PD-1 monoclonal antibody for injection (JS001) in combination with regorafenib tablet

Drug: JS001; Drug: regorafenib tablet

Interventions

JS001 DRUG

JS001 3 mg/kg, iv drip, d1, d15, q4w

Also known as: recombinant humanized anti-PD-1 monoclonal antibody for injection

JS001/regorafenib

regorafenib tablet DRUG

80/120/160 mg, po, d1-d21, Q4w.

Also known as: STIVARGA

JS001/regorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Males and females aged ≥18 years;
• Histologically or cytologically confirmed colon or rectal adenocarcinoma, with unresectable relapsed or metastatic disease;
• Microsatellite stability (MSS) or microsatellite instability-low (MSI-L), or proficient expression of DNA mismatch repair gene (pMMR);
• Patients who have failed, or can not tolerate after previous systemic treatment for relapsed or metastatic colorectal cancer, with no more than 3 months for disease progression after the last systemic treatment. The systemic treatment must contain fluorouracil, oxaliplatin and irinotecan, with or without targeted therapy (bevacizumab, cetuximab, and so on);
• With at least 1 measurable lesion according to RECIST 1.1 criteria; 1) Non-nodal lesions with the maximum diameter ≥10mm, or nodal lesions with the short axis ≥15mm; 2) For lesions previously treated locally with radiotherapy or ablation, if there is definite progression according to RECIST 1.1, and the maximum diameter ≥10mm, these can also be considered as measurable target lesions.
• ECOG score 0-1;
• Expected survival ≥3 months;
• Good organ function (without blood transfusion, use of hematopoietic stimulating factors, or transfusion of albumin or blood products within 14 days prior to examination):
• \) Platelet (PLT) count ≥100,000 /mm3; 2) Neutrophil count (ANC) ≥1,500 /mm3; 3) Hemoglobin (Hb) level ≥9.0 g/dl; 4) International normalized ratio (INR) ≤1.5; 5) Prothrombin time (PT) and activated partial thromboplastin time (APTT) ≤1.5×ULN; 6) Glycosylated hemoglobin (HbA1c) \<7.5%; 7) Total bilirubin (TBIL) level ≤1.5×ULN; 8) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) level ≤2.5×ULN (≤5×ULN in case of liver metastasis); 9) Alkaline phosphatase level ≤2.5×ULN (≤5×ULN in case of liver metastasis); 10) Serum creatinine (Cr) level ≤1.5×ULN and creatinine clearance ≥60 ml/min; 11) Thyroid stimulating hormone (TSH) ≤ULN; 12) Normal serum free thyroid hormone (T4); 13) Normal serum free triiodothyronine (T3); 14) Serum amylase ≤1.5×ULN; 15) Lipase ≤1.5×ULN. 9. Females of child bearing age must have a negative pregnancy test, and have to take contraception measures and avoid breast feeding during the study and for 3 months after the last dose; male subjects must agree to taken contraception measures during the study and for 3 months after the last dose.
• \. Able to understand and willing to sign written informed consent form.

You may not qualify if:

• Diagnosis of any other malignancy at different primary site or of different histological type from colorectal cancer within 5 years prior to initiation of study treatment, except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of cervix;
• Microsatellite instability-high (MSI-H) or deficient expression of DNA mismatch repair gene (dMMR);
• Previous treatment with regorafenib, PD-1/PD-L1/PD-L2 antibody or any other antibody that acts on T cell costimulatory or checkpoint pathways;
• Known allergy to study drug or excipients, or allergy to similar drugs;
• Have received other anti-tumor treatment within 4 weeks prior to initiation of study treatment, or no more than 5 half lives from the last dose;
• Have participated in other clinical study and received drug within 4 weeks prior to initiation of study treatment;
• Have undergone major surgery or open biopsy, or have massive trauma within 4 weeks prior to initiation of study treatment;
• Have received immunosuppressants (excluding inhaled corticosteroids or ≤10 mg/day prednisone or other systemic steroids at equivalent pharmaphysiological dose) within 2 weeks prior to initiation of study treatment;
• Have vaccination with attenuated live vaccines within 4 weeks prior to initiation of the study treatment or plan to vaccinate during the study;
• CYP3A4 inducers or inhibitors should not be stopped within 1 week prior to initiation of study treatment and during the study;
• Known metastasis to central nervous system;
• Present or history of any autoimmune disease;
• Human immunodeficiency virus (HIV) infection (HIV antibody positive), or active hepatitis C virus (HCV) infection (HCV antibody positive), or active hepatitis B virus (HBV) infection (HBsAg or HBcAb positive, and HBV-DNA ≥2000 IU/ml (copies/ml)), or other severe infection requiring systemic antibiotic treatment, or unexplained body temperature \>38.5℃ during screening period/before study treatment;
• Presence of pleural effusion, peritoneal effusion, or pericardial effusion;
• Development of the following diseases within 6 months prior to initiation of study treatment: myocardial infarction, severe/unstable angina, congestive heart failure above NYHA grade 2, poorly controlled arrhythmia;

Sponsors & Collaborators

• Sun Yat-sen University: lead
• Shanghai Junshi Bioscience Co., Ltd.: collaborator

Study Sites (1)

Sun Yat-sen University Cancer Center

Guangzhou, Guangdong, 510060, China

Location

Related Publications (5)

• Yoshino T, Komatsu Y, Yamada Y, Yamazaki K, Tsuji A, Ura T, Grothey A, Van Cutsem E, Wagner A, Cihon F, Hamada Y, Ohtsu A. Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations. Invest New Drugs. 2015 Jun;33(3):740-50. doi: 10.1007/s10637-014-0154-x. Epub 2014 Sep 12.

  PMID: 25213161 RESULT

• Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. doi: 10.1016/S1470-2045(15)70156-7. Epub 2015 May 13.

  PMID: 25981818 RESULT

• McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, Powderly JD, Infante JR, Fasso M, Wang YV, Zou W, Hegde PS, Fine GD, Powles T. Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study. J Clin Oncol. 2016 Mar 10;34(8):833-42. doi: 10.1200/JCO.2015.63.7421. Epub 2016 Jan 11.

  PMID: 26755520 RESULT

• Tang B, Yan X, Sheng X, Si L, Cui C, Kong Y, Mao L, Lian B, Bai X, Wang X, Li S, Zhou L, Yu J, Dai J, Wang K, Hu J, Dong L, Song H, Wu H, Feng H, Yao S, Chi Z, Guo J. Safety and clinical activity with an anti-PD-1 antibody JS001 in advanced melanoma or urologic cancer patients. J Hematol Oncol. 2019 Jan 14;12(1):7. doi: 10.1186/s13045-018-0693-2.

  PMID: 30642373 RESULT

• Yaghoubi N, Soltani A, Ghazvini K, Hassanian SM, Hashemy SI. PD-1/ PD-L1 blockade as a novel treatment for colorectal cancer. Biomed Pharmacother. 2019 Feb;110:312-318. doi: 10.1016/j.biopha.2018.11.105. Epub 2018 Dec 3.

  PMID: 30522017 RESULT

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Injections; regorafenib

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Rui-hua Xu, PhD

  Sun Yat-sen University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Principal Investigator, President

Study Record Dates

• First Submitted: April 14, 2019
• First Posted: May 13, 2019
• Study Start: March 12, 2019
• Primary Completion: May 1, 2020
• Study Completion: November 20, 2021
• Last Updated: May 12, 2020

Record last verified: 2020-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)