Study to Evaluate the Safety, Tolerability, Preliminary Efficacy and Pharmacokinetics of Simmitecan Monotherapy and Combination in Patients With Advanced Solid Tumors

NCT02870036 | Unknown Phase 1 DMC

• 1 other identifier: GV-LP-102
• Study Type: interventional
• Target: 243
• Locations: 1 country
• Sites: 9

Brief Summary

This study evaluates the safety, tolerability, preliminary efficacy and pharmacokinetics of Simmitecan in patients with advanced solid tumors and Simmitecan, 5-fluorouracil and Leucovorin Calcium,thalidomide in patients with advanced solid tumor or advanced/metastatic colorectal cancer.

Conditions

Advanced Solid Tumor; Advanced/Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (7)

• Cmax (maximum plasma concentration)

  before administration (within 5 minutes before administration), 45 and 90 minutes after the start of the infusion of Simmitecan and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48 and 72 hours after the completion of infusion of Simmitecan

• Tmax (time to maximum plasma concentration)

  before administration (within 5 minutes before administration), 45 and 90 minutes after the start of the infusion of Simmitecan and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48 and 72 hours after the completion of infusion of Simmitecan

• AUC (area under the plasma concentration-time curve)

  before administration (within 5 minutes before administration), 45 and 90 minutes after the start of the infusion of Simmitecan and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48 and 72 hours after the completion of infusion of Simmitecan

• T½

  before administration (within 5 minutes before administration), 45 and 90 minutes after the start of the infusion of Simmitecan and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48 and 72 hours after the completion of infusion of Simmitecan

• CL (systemic clearance)

  before administration (within 5 minutes before administration), 45 and 90 minutes after the start of the infusion of Simmitecan and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48 and 72 hours after the completion of infusion of Simmitecan

• Vz (apparent volume of distribution)

  before administration (within 5 minutes before administration), 45 and 90 minutes after the start of the infusion of Simmitecan and at 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48 and 72 hours after the completion of infusion of Simmitecan

• Adverse events (AE)

  AEs will be classified by type, incidence, severity (graded per NCI-CTCAE [version 4.03]), time to onset, seriousness and relationship

Secondary Outcomes (6)

• Objective response rate (ORR)

  Imaging examination will be performed for tumor assessment every 6 weeks (±7 days) from the first dose of Simmitecan until PD, intolerable toxicity, withdrawal of consent or death.

• progression free survival (PFS)

  Imaging examination will be performed for tumor assessment every 6 weeks (±7 days) from the first dose of Simmitecan until PD, intolerable toxicity, withdrawal of consent or death.

• CBR (clinical benefit rate)

  Imaging examination will be performed for tumor assessment every 6 weeks (±7 days) from the first dose of Simmitecan until PD, intolerable toxicity, withdrawal of consent or death.

• DCR (disease control rate)

  Imaging examination will be performed for tumor assessment every 6 weeks (±7 days) from the first dose of Simmitecan until PD, intolerable toxicity, withdrawal of consent or death.

• OS (overall survival)

  Imaging examination will be performed for tumor assessment every 6 weeks (±7 days) from the first dose of Simmitecan until PD, intolerable toxicity, withdrawal of consent or death.

Study Arms (6)

Pharmacokinetic data investigation of Simmitecan

EXPERIMENTAL

To further determine the pharmacokinetic (PK) characteristics of Simmitecan monotherapy in patients with advanced solid tumors

Drug: Simmitecan

Dose escalation study of Simmitecan combined therapy

EXPERIMENTAL

To determine the maximum tolerated dose (MTD) of Simmitecan combined with 5-fluorouracil/Leucovorin Calcium in patients with advanced solid tumor

Drug: Simmitecan; Drug: 5-fluorouracil and Leucovorin Calcium

Dose extension study of Simmitecan monotherapy

EXPERIMENTAL

To preliminarily evaluate the anti-tumor activity of Simmitecan monotherapy in patients with advanced solid tumors, and to determine the recommended phase II dose (RP2D)

Drug: Simmitecan

Dose extension study of Simmitecan combined Thalidomide

EXPERIMENTAL

To preliminarily evaluate the anti-tumor activity of Simmitecan combined with 5-fluorouracil/Leucovorin Calcium in patients with advanced/metastatic colorectal cancer (CRC), and to determine RP2D

Drug: Simmitecan; Drug: Thalidomide

Dose escalation&extension Simmitecan combined Thalidomide

EXPERIMENTAL

To preliminarily evaluate the anti-tumor activity of Simmitecan combined with thalidomide in patients with gastrointestinal tumors, and to determine RP2D and MTD

Drug: Simmitecan; Drug: Thalidomide

Dose extension study of Simmitecan combined therapy

EXPERIMENTAL

To preliminarily evaluate the anti-tumor activity of Simmitecan combined with thalidomide in patients with specific tumors

Drug: Simmitecan; Drug: 5-fluorouracil and Leucovorin Calcium

Interventions

Simmitecan DRUG

Dose escalation study of Simmitecan combined therapy; Dose escalation&extension Simmitecan combined Thalidomide; Dose extension study of Simmitecan combined Thalidomide; Dose extension study of Simmitecan combined therapy; Dose extension study of Simmitecan monotherapy; Pharmacokinetic data investigation of Simmitecan

5-fluorouracil and Leucovorin Calcium DRUG

Dose escalation study of Simmitecan combined therapy; Dose extension study of Simmitecan combined therapy

Thalidomide DRUG

Dose escalation&extension Simmitecan combined Thalidomide; Dose extension study of Simmitecan combined Thalidomide

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who have fully understood the study, and are willing to sign the informed consent (ICF);
• Patients with advanced solid tumor confirmed by histopathology and/or cytology were enrolled in Parts 1 and 2 of the study; Four groups of patients with advanced solid tumor confirmed by histopathology and/or cytology were enrolled in Part 3 of the study: Group 1 consisted of patients with rectal carcinoma, Group 2 consisted of patients with gastric carcinoma and esophageal carcinoma, Group 3 consisted of patients with biliary duct carcinoma and pancreatic carcinoma, and Group 4 consisted of patients with gastro-entero-pancreatic neuroendocrine carcinoma. Patients with advanced or metastatic CRC confirmed by histopathology and/or cytology were enrolled in Part 4 of the study; In Part 5 of the study, patients with advanced gastrointestinal tumor (including biliary tumor \[gallbladder carcinoma, intra- or extra-hepatic biliary carcinoma\], pancreatic carcinoma, hepatocellular carcinoma, esophageal carcinoma, gastric carcinoma, colorectal carcinoma, gastrointestinal stromal carcinoma, and gastro-entero-pancreatic neuroendocrine carcinoma) confirmed by histopathology were enrolled; In Part 6 of the study, patients with advanced gastrointestinal tumor (tentatively determined as biliary tumor, hepatocellular carcinoma, pancreatic carcinoma, and colorectal carcinoma); At least 5 unstained slices of tumor tissues must be obtained at baseline from patients participating in Parts 5 and 6 of the study: Primary lesion samples at the initial diagnosis or archived recently were acceptable. They were used to detect protein expression level of SOD1 and other related molecules to and tumor immunity related indicators.
• Note: patients being enrolled in part 2 of the study should be those with advanced solid tumor who are suitable for therapeutic regimen of Simmitecan combined with 5 FU/LV as judged by the investigator;
• Patients who had failed standard treatments for advanced cancer, or are intolerant to the current standard treatments, or no suitable standard treatments available for advanced cancer;
• Patients who have at least one measurable lesion (according to RECIST, version 1.1); note: the lesions previously treated with radiotherapy cannot be regarded as the target lesion, unless the lesion showed clear progression after radiotherapy;
• Patients with Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
• Age≥ 18 years and ≤ 70 years, male or female is allowed;
• Patients with life expectancy of 12 weeks or more;
• Patients with appropriate organ function as documented by:
• absolute neutrophil count ≥ 1.5 × 109/L;
• hemoglobin ≥ 9 g/dL (without RBC transfusion within 14 days);
• platelet count ≥ 100 × 109/L.
• serum total bilirubin ≤1.5 times of upper limit of normal (ULN) (for the patients with Gilbert syndrome, total bilirubin is allowed to be ≤ 3 × ULN and direct bilirubin is allowed to be 1.5 × ULN);
• aspertate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × ULN, or AST and ALT ≤ 5 × ULN for patients with liver metastasis;
• creatinine clearance ≥ 50 mL/min (calculated by MDRD equation, see appendix 7);

You may not qualify if:

• Patients are still within 5 half-life of previous anticancer chemotherapy, biological agents or other investigational drugs (if 5 half-life exceeds 28 days, calculated as 28 days) at the time of screening;
• Patients received systemic radiotherapy (including whole brain radiotherapy) within 28 days before enrollment, or received small area radiotherapy (stereotactic radiotherapy of central nervous system (CNS)) within 7 days before enrollment, or have not yet recovered from the previous radiotherapy;
• Patients have not yet recovered from the toxic effects (except alopecia) caused by previous anti-tumor treatments (\> CTCAE grade 1);
• Patients underwent major surgery or have not yet been fully recovered from pervious surgery (major surgery is defined as grade 3 or 4 surgery specified in "Management Measures for Clinical Application of Medical Technology" implemented on May 1st, 2009).
• Patients had CNS metastasis or cancer-related epilepsy requiring clinical intervention; however, patients with CNS metastasis who received treatments, or the asymptomatic patient can be enrolled;
• Patients with a history of allergy to 5-FU or LV;
• Patients with active HBV or HCV infection;
• Patients diagnosed as human immunodeficiency virus (HIV) infection, or are not willing to have HIV test;
• Patients with clinically significant active infection;
• Patients with previous or concurrent other malignant tumors (except effectively controlled non-melanoma skin basal cell carcinoma, breast/cervical carcinoma in situ, and other effectively controlled tumors in the past 5 years even without treatments);
• Patients with impaired cardiac function or clinically significant heart diseases, including grade 2 or higher congestive heart failure per New York Heart Association (NYHA) classification, arrhythmia, conduction abnormalities requiring treatment, cardiomyopathy, or uncontrolled hypertension;
• Patients with serious kidney damage requiring kidney dialysis;
• Patients with serious liver damage, grade B or C end-stage liver diseases per Child-Pugh classification (see appendix 8);
• Any other diseases or conditions with clinical significance that may affect the protocol compliance or patient's signature of ICF at the investigator's discretion (such as uncontrolled diabetes, etc.);
• Patients with disease of digestive tract such as duodenal ulcer, ulcerative colitis, intestinal obstruction or other conditions that may cause alimentary tract hemorrhage or perforation as judged by the investigator, or have past medical history of gastric-intestinal perforation or intestinal fistula;;

Sponsors & Collaborators

• Haihe Biopharma Co., Ltd.: lead

Study Sites (9)

Beijing Cancer Hospital

Beijin, Beijing Municipality, 100000, China

RECRUITING

Harbin Medical University Cancer Hospital

Harbin, Heilongjiang, China

NOT YET RECRUITING

Tongji Hospital of Tongji Medical College,Huazhong University of Science and Technology

Wuhan, Hubei, 430030, China

NOT YET RECRUITING

Hunan Cancer Hospital

Changsha, Hunan, 410013, China

NOT YET RECRUITING

Jiangsu Cancer Hospital

Nanjing, Jiangsu, China

NOT YET RECRUITING

The first hospital of China Medical University

Shenyang, Liaoning, 110001, China

NOT YET RECRUITING

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, 200000, China

NOT YET RECRUITING

Tianjin Cancer Hospital

Tianjin, Tianjin Municipality, 300060, China

NOT YET RECRUITING

The Second Affiliated hospital of Zhejiang University School of Medicine

Hangzhou, Zhejiang, 50011, China

NOT YET RECRUITING

Related Publications (2)

• Guimbaud R, Louvet C, Ries P, Ychou M, Maillard E, Andre T, Gornet JM, Aparicio T, Nguyen S, Azzedine A, Etienne PL, Boucher E, Rebischung C, Hammel P, Rougier P, Bedenne L, Bouche O. Prospective, randomized, multicenter, phase III study of fluorouracil, leucovorin, and irinotecan versus epirubicin, cisplatin, and capecitabine in advanced gastric adenocarcinoma: a French intergroup (Federation Francophone de Cancerologie Digestive, Federation Nationale des Centres de Lutte Contre le Cancer, and Groupe Cooperateur Multidisciplinaire en Oncologie) study. J Clin Oncol. 2014 Nov 1;32(31):3520-6. doi: 10.1200/JCO.2013.54.1011. Epub 2014 Oct 6.

  PMID: 25287828 BACKGROUND

• Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ, He J. Cancer statistics in China, 2015. CA Cancer J Clin. 2016 Mar-Apr;66(2):115-32. doi: 10.3322/caac.21338. Epub 2016 Jan 25.

  PMID: 26808342 RESULT

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

simmitecan; Fluorouracil; Leucovorin; Thalidomide

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)

Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Isoindoles

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 3, 2016
• First Posted: August 17, 2016
• Study Start: October 1, 2016
• Primary Completion: December 1, 2020
• Study Completion: December 1, 2020
• Last Updated: July 14, 2017

Record last verified: 2017-07

Locations

CN (9)