Neoplasms

Digestive System Diseases

All Conditions

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

All Drugs and Chemicals

Antibodies

Antibodies, Monoclonal

Immunoglobulins

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

JS001

regorafenib tablet

Rui-hua Xu, PhD

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.

Colorectal cancer is one of the most common malignancies in China, with incidence and mortality ranking the 3rd and 4th among malignancies in China. Regorafenib is the standard multi-kinase inhibitor for refractory metastatic colorectal cancer, with multiple anti-tumor effects by inhibiting targets related to tumor cell proliferation, tumor metastasis, tumor angiogenesis and tumor immune escape, howerver, its efficacy is limited. Immunotherapy has become standard treatment for mCRC patients with MSI-H/dMMR. Combination of anti-angiogenesis treatment and immunotherapy may have a better anti-tumor effect. 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.

JS001 Combined With Regorafenib in Patients With Advanced Colorectal Cancer

A Multi-center, Open-label, Phase I/II Clinical Trial of Tolerability, Safety and Efficacy of Recombinant Humanized Anti-PD-1 Monoclonal Antibody for Injection (JS001) Combined With Regorafenib in Patients With Advanced Colorectal Cancer

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

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

The ratio of patients who are evaluated as CR or PR

The Kaplan-Meier survival from the initiation date of first cycle until the date of first documented progression or date of death

The Kaplan-Meier survival from the initiation date of first cycle until death from any cause or the last follow-up date.

Defined as the proportion of patients whose tumors shrink or remain stable for a certain period of time, including CR, PR and SD.

defined as the time between the first assessment of a tumor as PR or CR and the first assessment as PD or any cause of death

The dynamic variation of circulating free DNA or cell free DNA (cfDNA) in immunotherapy efficacy and safety assessment

The composition of intestinal microorganism pre- and post-treatment tested by intestinal microorganism, the relationship between intestinal flora alpha diversity and beta diversity and immunotherapy response as well as between intestinal microorganism alpha diversity and beta diversity and treatment toxicity and tolerance.

Shanghai Junshi Bioscience Co., Ltd.

Sun Yat-sen University

Professor, Principal Investigator, President

Musculoskeletal Diseases

Skin and Connective Tissue Diseases

Rare Diseases

Sarcoma

Osteosarcoma

Sarcoma, Ewing

Bone Neoplasms

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Bone Diseases

Soft Tissue Sarcoma

Ewing Sarcoma

Standard ES treatment consists of: induction chemotherapy (VDC/IE) and local treatment (surgery/radiotherapy), followed by consolidation chemotherapy (VC/IE)/ Bu-Mel (according to physician and patient choice).

Regorafenib will be administered during induction chemotherapy (VDC/IE) and during consolidation chemotherapy with conventional chemotherapy (VC/IE) but not Bu-Mel therapy Conventional chemotherapy will be administered at the recommended dose (100%) and only regorafenib will be escalated/de-escalated.

Regorafenib will only be given concomitant to radiotherapy in case the primary tumor is located in the extremities. In case of primary tumors located in the pelvis, abdomen, thorax, spine, brain, head or neck, regorafenib will be stopped at least 1 week before start of radiotherapy.

Regorafenib will be escalated/de-escalated, starting at DL0:

* DL1: 82 mg/m\^2 once daily for 21 days/28 days (max 160mg) (100% of the RP2D)
* DL0 (starting dose): 66 mg/m\^2 once daily for 21 days/28 days (max 120mg) (80% of the RP2D)
* DL-1: 50 mg/m\^2 once daily for 21 days/28 days (max 80mg) (60% of the RP2D)

Pablo Berlanga, MD

New drug efficacy in ES has been disappointing in the last decades and no new drugs have been successfully introduced up to now in front line treatment. Among the tested drugs, early clinical data suggest that strategies using multi-targeted tyrosine kinase inhibitors (TKI) with anti-angiogenic activities are among the most efficient and may be beneficial in the treatment of patients with ES.

Several TKI have been and are currently being tested as single-agent in patients with relapsed/refractory ES with encouraging results in phase II trials. Regorafenib has shown promising activity in Ewing sarcoma relapse setting, Nevertheless, regorafenib has never been combined with the intensive chemotherapy VDC/IE schedule and therefore this combination needs to be evaluated in order to avoid dose reduction of the current standard treatment and hence its efficacy.

The current clinical trial has been therefore designed to test the feasibility of regorafenib with ES conventional chemotherapy. It consists of a phase Ib that will only recruit patients with multi-metastatic (other than lungs/pleura only) ES, that present the highest unmet medical need (2 year EFS: 33%, similar to patients with relapse/refractory ES).

All included patients will receive standard Ewing sarcoma (ES) treatment concomitant with regorafenib.

Standard ES treatment consists of: induction chemotherapy (VDC/IE) and local treatment (surgery/radiotherapy), followed by consolidation chemotherapy (VC/IE)/ Bu-Mel (according to physician and patient choice).

Regorafenib will be administered during induction chemotherapy (VDC/IE) and during consolidation chemotherapy with conventional chemotherapy (VC/IE) but not Bu-Mel therapy

Conventional chemotherapy will be administered at the recommended dose (100%) and only regorafenib will be escalated/de-escalated, starting at DL0:

* DL1: 82 mg/m\^2 once daily for 21 days/28 days (max 160mg) (100% of the RP2D)
* DL0 (starting dose): 66 mg/m\^2 once daily for 21 days/28 days (max 120mg) (80% of the RP2D)
* DL-1: 50 mg/m\^2 once daily for 21 days/28 days (max 80mg) (60% of the RP2D) Regorafenib will be stopped 2 weeks before planned surgery of the primary tumor and reintroduced when adequate wound healing is obtained, concomitant with consolidation VC/IE chemotherapy.

Regorafenib will only be given concomitant to radiotherapy in case the primary tumor is located in the extremities. In case of primary tumors located in the pelvis, abdomen, thorax, spine, brain, head or neck, regorafenib will be stopped at least 1 week before start of radiotherapy.

Patient with Ewing Sarcoma male or female age ≥2 years and \<50 years (from second birthday to 49 years 364 days) who are assessed as medically fit to receive the Ewing sarcoma standard multimodal treatment and regorafenib. Patients will benefit from the social security coverage in force in their country and will have received free and informed information allowing the collection of their consent.

Phase Ib / Regorafenib With Conventional Chemotherapy/Newly Diagnosed Patients/ Multimetastatic Ewing Sarcoma

Phase Ib Study of the Combination of Regorafenib With Conventional Chemotherapy for the Treatment of Newly Diagnosed Patients With Multimetastatic Ewing Sarcoma

The dose-finding escalation will be driven by the occurrence of Dose-Limiting Toxicities (DLT), assessed over the first 28-day cycle (cycle 1), and defined as any of the following haematological and non-haematological events that occur during the DLT period (4 weeks after the start of treatment = cycle 1) and are at least possibly related (possibly, probably, or definitely) attributable to VDC/IE + regorafenib:

* Any cardiac toxicity grade ≥ 3
* Any grade 3 or 4 (hematological or non-hematological) toxicity leading to delay of start of next course by \> 7 days (i.e: starting \> day 21).
* Any dose interruption or reduction due to toxicity which results in administration of less than 80% of the planned dosage of regorafenib or 75% of the planned dosage of chemotherapy.
* Any grade 3 or 4 toxicity resulting in discontinuation of the new combination
* Any grade 5 toxicity related to study treatment (death)

Defined as the time from start of anti-cancer treatment to death, irrespective of the cause. Surviving patients will be censored at their last follow-up date

Defined as the time from start of anti-cancer treatment to first event, where an event is progression without complete remission, recurrence following complete remission or death.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
JS001 Combined With Regorafenib in Patients With Advanced Colorectal Cancer	NCT03946917	Colorectal Canc...	JS001 regorafenib tab...	18 Years -	Sun Yat-sen University
Phase Ib / Regorafenib With Conventional Chemotherapy/Newly Diagnosed Patients/ Multimetastatic Ewing Sarcoma	NCT05830084	Bone Cancer	regorafenib tab...	2 Years - 50 Years	Gustave Roussy, Cancer Campus, Grand Paris

Spots Global Cancer Trial Database for regorafenib tablet