Safety and Efficacy of FOLFSIM Plus Toripalimab in the Treatment of Advanced or Metastatic Neuroendocrine Carcinoma

Phase II/III Trial of Simmtecan and 5-FU/LV Regimen (FOLFSIM) Plus Teripalimab Versus EP/EC in Advanced or Metastatic Neuroendocrine Carcinoma

This study is designed as Phase II/III. Phase II is aimed to evaluate safety and efficacy of Simmtecan and the 5-FU/LV regimen (FOLFSIM regimen) plus Toripalimab. Phase III is aimed to verify inferiority of the overall survival of FOLFSIM regimen plus Toripalimab in comparison with EP/EC in advanced or metastatic neuroendocrine cancer.

Study Overview

• Status: Recruiting
• Conditions: Neuroendocrine Carcinoma of the Bladder
• Intervention / Treatment: Drug: Simmtecan, 5-FU and l-LV; Drug: Toripalimab; Drug: Etoposide, Cisplatin; Drug: Etoposide, Carboplatin

Detailed Description

This is a Phase II/III, randomized, two-part, multi-center study, in which subjects with advanced or metastatic neuroendocrine carcinoma will be enrolled.

This study will be conducted in two parts:

Part 1, the Phase II study was to: (i) evaluate the safety and tolerability of the FOLFSIM regimen plus Toripalimab; and (ii) identify the recommended dose; (iii) assess the antitumor activity; (iv) the pharmacokinetic (PK) parameters of the drugs in the regimen.

Part 2, the Phase III study was to verify inferiority of FOLFSIM regimen plus Toripalimab compared with the current standard chemotherapy (EP/EC regimen) in the first-line treatment of advanced or metastatic neuroendocrine carcinoma.

• Study Type: Interventional
• Enrollment (Anticipated): 336
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100142
      • Recruiting
      • Beijing Cancer Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Signed informed-consent form.
2. Male and Female aged between 18-75 years.
3. Histologically confirmed locally advanced or metastatic nonfunctional poorly-differentiated G3 neuroendocrine carcinoma(NEC), including small cell NEC, large cell NEC and MANEC.

4. Unresectable, including local advanced, recurrent or metastatic disease:

   Patients who had progressed after first-line platinum-based regimen or intolerance for treatment, or unwilling to receive current standard chemotherapy (only for phase II); Patients who has received no systemic chemotherapy, or relapsed at least 6 months since completion of adjuvant chemotherapy or radiotherapy.

5. At least 1 measurable lesion according to RECIST criteria;
6. Providing with tumor specimen (for testing the expression of PD L1 and the infiltrating lymphocytes);
7. Eastern Cooperative Oncology Group (ECOG) 0-1;
8. Adequate liver, kidney and bone marrow function; Screening laboratory values must meet the following criteria: hemoglobin ≥ 10.0 g/dL; neutrophils ≥ 1500 cells/ μL; platelets ≥ 100 x 10^3/ μL; total bilirubin ≤ 1.5 x upper limit of normal (ULN); aspartic transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN without, and ≤ 5 x ULN with hepatic metastasis; serum creatinine ≤1.5 x ULN, creatinine clearance >60ml/min (CockcroftGault equation), INR≤1.5, APTT≤1.5 x ULN;

Exclusion Criteria:

1. Histologically confirmed well differentiated G3 neuroendocrine tumor;
2. Evidence with active CNS disease or epilepsy;
3. Metastasis over 5 lesions;
4. Prior treatment with CPT-11 or antiPD1/PDL1/CTLA-4 antibody for neoadjuvant or adjuvant therapy;
5. Prior malignancy active within the previous 5 years except for locally curable cancers that have been apparently cured, such as basal cell skin cancer or carcinoma in situ of the cervix;
6. Predicted survival <3 months;
7. Severe, uncontrolled medical condition that would affect patients' compliance or obscure the interpretation of toxicity determination or adverse events, including active severe infection, uncontrolled diabetes, angiocardiopathy (heart failure > class II NYHA, heart block >II grade, myocardial infarction, unstable arrhythmia or unstable angina within past 6 months, cerebral infarction within past 3 months) or pulmonary disease ( interstitial pneumonia, obstructive pulmonary disease or symptomatic bronchospasm);
8. Any uncontrollable active infection, within past 1 week
9. Patients with any active autoimmune disease or a documented history of autoimmune disease, or history of syndrome that required systemic steroids or immunosuppressive medications, such as hypophysitis, pneumonia, colitis, hepatitis, nephritis, hyperthyroidism or hypothyroidism;
10. History with tuberculosis;
11. The side effects caused by the previous treatment of the subjects did not return to CTCAE ≤1; except hair loss and other tolerable events determined by investigator;
12. Hypersensitivity to Simmtecan or recombinant humanized antiPD1 monoclonal Ab or its components;
13. Prior antitumor therapy (including chemotherapy, target therapy, corticosteroids and immunotherapy) or participation in other clinical trials within past 4 weeks, or have not recovered from toxicities since the last treatment;
14. Patients who received a potent inhibitor or inducer of CYP3A4 within 1 week prior to the first dose;
15. Prior radical radiothearpy within past 4 weeks;
16. Prior major surgery within past 4 weeks (diagnostic surgery excluded);
17. Prior live vaccine therapy within past 4 weeks;
18. Positive tests for HIV, HCV, HBsAg or HBcAb with positive test for HBV DNA (>500IU/ml);
19. Pregnant or nursing;
20. Males or female of childbearing potential refuse to use using a reliable form of contraception (eg, oral contraceptives, intrauterine device, control sex desire, double barrier method of condom and spermicidal) during the treatment period and for at least 12 months after the last dose of study drug.
21. Underlying medical condition that, in the Investigator's opinion, would increase the risks of study drug administration or obscure the interpretation of toxicity determination or adverse events.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FOLFSIM Plus Teripalimab; Simmtecan and 5-FU/LV Regimen (FOLFSIM) Plus Teripalimab	Drug: Simmtecan, 5-FU and l-LV; Simmtecan was administered intravenously at 80 mg per square meter on day1 with LV 400 mg per square meter administered as a 2-hour infusion, and 5-FU 2400 mg per square meter as a 46-hour infusion on day1 every 2 weeks in one course.; Other Names: FOLFSIM regimen; Drug: Toripalimab; Toripalimab was administered intravenously at 240 mg on day 1 every 2 weeks in one course.; Other Names: JS001
Active Comparator: EP/EC; Etoposide plus Cisplatin or Carboplatin	Drug: Etoposide, Cisplatin; Etoposide was administered intravenously at 100 mg per square meter on day 1,2,3 with Cisplatin at 80 mg per square meter on day 1 every 3 weeks in one course.; Other Names: EP regimen; Drug: Etoposide, Carboplatin; Etoposide was administered intravenously at 100 mg per square meter on day 1,2,3 and Carboplatin with AUC 5mg/mL/min on day 1 every 3 weeks in one course.; Other Names: EC regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Measure of time from study treatment to patient's death or lost to follow-up.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Measure of time from study treatment to disease progression or death.	2 years
Objective response rate	Percentage of patients who achieve partial response (PR) or complete response (CR) based on Response Evaluation Criteria In Solid Tumors (RECIST)	2 years
Disease control rate	The sum of rates of partial response, complete response and steady disease based on Response Evaluation Criteria In Solid Tumors (RECIST).	2 years
Duration of response	Duration of Response by RECIST	2 years
The incidence of treatment related emergent adverse events（Safety and Tolerance)	Adverse reactions evaluation is based on the CTCAE	2 years

Collaborators and Investigators

• Sponsor: Peking University
• Investigators: Principal Investigator: Lin Shen, Peking University

Study record dates

Study Major Dates

• Study Start (Actual): June 19, 2019
• Primary Completion (Anticipated): June 20, 2022
• Study Completion (Anticipated): June 20, 2023

Study Registration Dates

• First Submitted: June 19, 2019
• First Submitted That Met QC Criteria: June 19, 2019
• First Posted (Actual): June 20, 2019

Study Record Updates

• Last Update Posted (Actual): June 20, 2019
• Last Update Submitted That Met QC Criteria: June 19, 2019
• Last Verified: June 1, 2019

More Information

Terms related to this study

• Keywords: Neuroendocrine Carcinoma; Toripalimab; Simmtecan
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Urinary Bladder Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Carcinoma; Urinary Bladder Neoplasms; Carcinoma, Neuroendocrine; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Carboplatin; Etoposide; Etoposide phosphate; Cisplatin
• Other Study ID Numbers: LP-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No