JS001 in Combination With RC48-ADC in Treatment of HER2-Positive Advanced Malignant Solid Tumors

• ClinicalTrials.gov Identifier: NCT04280341
• Recruitment Status: Unknown
• First Posted: February 21, 2020
• Last Update Posted: February 21, 2020
• Sponsor: Peking University
• Collaborator: RemeGen Co., Ltd.
• Information provided by (Responsible Party): Shen Lin, Peking University

Study Description

Brief Summary:

This is a non-randomized, open-label, single-arm, multicenter Phase I clinical trial which will evaluate the Safety, Efficacy, Tolerability and Pharmacokinetics of RC48-ADC in combinaton with Anti-PD1 Monoclonal Antibody in Treatment of HER2-Positive Advanced Malignant Solid Tumors.

Condition or disease	Intervention/treatment	Phase
HER2-Positive Solid Tumors	Biological: RC48-ADC in combinaton with JS001	Phase 1

Detailed Description:

The study has 2 parts which include dose escalation phase and dose extension phase.

Dose escalation will use a 3+3 design and will enroll cohorts of 3-6 patients with HER2-Positive Advanced Malignant Solid Tumors sequentially at escalating doses of 2.0mg/kg and 2.5mg/kg to RC48-ADC and JS001 is fixed dose of 3.0mg/mg . Escalation will continue until identification of a MTD.

Dose of phase II and extenstion stage which based-results of escalation phase will be recommend.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I, Open-label, Dose Escalation Clinical Trial to Assess the Safety, Efficacy, Tolerability and Pharmacokinetics of the Recombinant Humanized Anti-PD1 Monoclonal Antiody (JS001) in Combination With Recombinant Humanized Anti-HER2 Monoclonal Antibody-MMAE Conjugate (RC48-ADC) in Treatment of HER2-Positive Advanced Malignant Solid Tumors
• Estimated Study Start Date: March 2020
• Estimated Primary Completion Date: December 2021
• Estimated Study Completion Date: December 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: RC48-ADC in combinaton with Anti-PD1 Monoclonal Antibody; RC48-ADC(Recombinant Humanized Anti-HER2 Monoclonal Antibody-MMAE Conjugate) JS001(Recombinant Humanized Anti-PD1 Monoclonal Antibody)	Biological: RC48-ADC in combinaton with JS001; The study has 2 parts which include dose escalation phase and dose extension phase. Dose escalation will use a 3+3 design and will enroll cohorts of 3-6 patients with HER2-Positive Advanced Malignant Solid Tumors sequentially at escalating doses of 2.0mg/kg and 2.5mg/kg to RC48-ADC and JS001 is fixed dose of 3.0mg/mg

Outcome Measures

Primary Outcome Measures :

1. DLT(dose-limiting toxicity) [ Time Frame: 28 days ]
   Side effects of drug or treatment that are serious enough to prevent an increase in dose or level of that treatment.
2. ORR [ Time Frame: From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months ]
   Percentage of patients who achieve partial response (PR) or complete response (CR) based on Response Evaluation Criteria In Solid Tumors (RECIST v1.1).
3. DOR [ Time Frame: From date of first dose until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 24 months ]
   The percentage of patients who achieve complete remission(CR) or partial remission (PR) or stable disease(SD) determined by the RECIST v1.1 criteria.

Secondary Outcome Measures :

1. PFSR of 6-month and 1-year [ Time Frame: 6 months and 12 months ]
   progression free survival rate
2. CBR(clinical benefit rate) [ Time Frame: up to 2 years ]
   The percentage of patients who have achieved complete response, partial response and stable disease to the therapeutic intervention.
3. adverse events [ Time Frame: 1 year ]
   Safety of participants followed for the duration of hospital stay, an expected average of 1 week
4. ADA [ Time Frame: up to 2 years ]
   anti-drug antibody which can result in treatment failure by blocking the pharmacological function of the drug.
5. NADA [ Time Frame: up to 2 years ]
   neutralizing anti-drug antibody which can result in treatment failure by blocking the pharmacological function of the drug.
6. Cmax [ Time Frame: up to 3 cycles(each cycle is 14 days) ]
   Peak plasma concentration
7. AUC [ Time Frame: up to 3 cycles(each cycle is 14 days) ]
   area under the plasma concentration versus time curve
8. Tmax [ Time Frame: up to 3 cycles(each cycle is 14 days) ]
   Time for peak concentration

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Willing to sign the informed consent form;
• ≥18 years old;
• Diagnosed histologically or cytologically with local advanced or metastatic HER2-positive malignant solid cancer( indicating that IHC result is 2+,3+or1+ ) and under one of following situations: standard treatment-refractory (disease progression or no response), treatment-resistant, unable to receive treatment, or the standard treatment is unavailable;
• Having measurable or evaluable lesions according to RECIST 1.1;
• Having an ECOG performance status score of 0 or 1;
• Echocardiographic LVEF (left ventricular ejection fraction) ≥ 50%.
• NYHA CLAS 0-1;
• Having sufficient bone marrow, liver and kidney functions (based on the normal value of the clinical trial site) within 7 days before erollment: Absolute neutrophil count (ANC) ≥ 1.5×109/L,Platelets ≥ 100×109/L, hemoglobin≥ 9.0 g/dL；Total serum bilirubin ≤ 1.5×upper limit of normal (ULN);Without liver metastasis, ALT, AST or ALP ≤ 2.5×ULN; With liver metastasis, ALT, AST or ALP ≤ 5×ULN;Serum creatinine clearance rate ≥ 60 mL/min(Cockcroft-Gault formula);INR International Normalized Ratio ≤ 1.5 × ULN, APTT ≤ 1.5 × ULN;
• With an expected survival of more than 3 months;
• Male or female patients of childbearing potential must agree to use effective methods of contraception (such as double-barrier contraceptive methods, condoms, oral or injectable contraceptives and intrauterine devices) during the study period and within 24 weeks after the last dosing;

Exclusion Criteria:

• Known active uncontrolled or symptomatic CNS metastases, as indicated by clinical symptoms, cerebral edema, spinal cord compression, carcinomatous meningitis, leptomeningeal disease and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated and are clinically stable o before the first dose of RC48-ADC.
• Prior treatment with HER2 targeted therapy while LVEF decline <45% or absolute value of LVEF decline >15%；
• Participation in any other studies within 4 weeks before study entry and/or during participation in the active treatment phase of the trial.
• Radical operation within 3 weeks before study entry but not include diagnostic puncture or peripheral vascular assess replacement ;
• Radical radiation therapy within 3 months before study entry; Patient of Palliative radiotherapy is eligible into this study if <30 % Radiation area of bone marrow;
• Patients who underwent checkpoint inhibitor or tumor vaccines include not limited PD-1、 PD-1、PD-L1、CTLA4、LAG3;
• Patient has had systemic steroid therapy (≥10 mg/day of prednisone or physiologic replacement doses of hydrocortisone, or its equivalent) or immunosuppressive medication within 14 days prior to the first dose of study.
• Live vaccines within 28 days prior to the first dose of study and during trial treatment.
• Patient has an active autoimmune disease or a documented history of autoimmune disease (but not limited In terstitial lung Disease, uveitis, SLE, etal). Patients with vitiligo or resolved childhood asthma/atopy would be exception to this rule. Patients that require inhaled steroids or local steroid injections would not be excluded from the study. Patients with vitiligo or psoriasis that is stable on hormone replacement will not be excluded from the study.
• Active and clinically significant bacterial, fungal or viral infection including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
• Patients have uncontrollable systemic disease which including diabetes, hypertendion, pulmonary fibrosis, etal.
• The toxicity of previous anti-cancer therapy has not returned to 0 or 1 level as specified in CTCAE v4.0 (except for hair loss);
• Patient has a history of allogeneic HSCT or organ transplation before study entry;
• Patients with hypersensitivity or delayed hypersensitivity reactions to certain components of RC48-ADC or similar drugs;
• Patients with symptomatic include but not limited ascites or pleural effusion and mental disease.

Contacts and Locations

Contacts

Contact: lin Shen, professor; 86-10-88196561; linshenpku@163.com

Sponsors and Collaborators

Peking University

RemeGen Co., Ltd.

Investigators

• Principal Investigator: Lin Shen, professor; Peking University

More Information

• Responsible Party: Shen Lin, MD，Professor,Chief of Department of GI Oncology,Peking University Cancer Hospital, Peking University
• ClinicalTrials.gov Identifier: NCT04280341
• Other Study ID Numbers: RC48-C013
• First Posted: February 21, 2020
• Last Update Posted: February 21, 2020
• Last Verified: February 2020

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Shen Lin, Peking University:

RC48-ADC; JS001; HER2 positive solid Tumor

Additional relevant MeSH terms:

Neoplasms