Fruquintinib in Combination With Sintilimab in Patients With Advanced Solid Tumor

• ClinicalTrials.gov Identifier: NCT03903705
• Recruitment Status: Unknown
• First Posted: April 4, 2019
• Last Update Posted: September 14, 2020
• Sponsor: Hutchison Medipharma Limited
• Information provided by (Responsible Party): Hutchison Medipharma Limited

Study Description

Brief Summary:

This study is composed of dose escalation stage and dose expansion stage. In dose escalation stage, patients with advanced solid tumor will be enrolled and administrated with Fruquintinib in combination with Sintilimab. The MTD ( maximum tolerated dose) or RP2D ( Recommended Phase 2 Dose) will be determined in this stage. In dose expansion stage, additional patients will be enrolled and be treated at RP2D to evaluate the safety, tolerability and efficacy.

Condition or disease	Intervention/treatment	Phase
Advanced Solid Tumor	Drug: Fruquintinib in Combination with Sintilimab	Phase 1; Phase 2

Detailed Description:

This study is composed of dose escalation stage and dose expansion stage. In dose escalation stage, 9-12 patients with advance solid tumor will be sequentially enrolled in Cohort A (Fruquintinib 3 mg QD (once a day), oral dosing, 3 weeks on/1 weeks off+Sintilimab 200mg Q4W(4 times a week), intravenous dosing) and Cohort B (Fruquintinib 4 mg QD, oral dosing, 3 weeks on/1 week off+Sintilimab 200mg Q4W, intravenous dosing). The MTD or RP2D will be determined in this stage. In dose expansion stage, 75 patients with advanced solid tumor will be enrolled and treated with RP2D. Efficacy, safety and tolerability will be assessed and PK (Pharmacokinetics) analysis will be performed in this study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 208 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Intervention Model Description: Open-Label Phase 1b/II Study of Fruquintinib in Combination with Sintilimab to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy in Patients with Advanced Solid Tumor.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Phase 1b/II Study of Fruquintinib in Combination With Sintilimab to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy in Patients With Advanced Solid Tumor
• Actual Study Start Date: April 25, 2019
• Estimated Primary Completion Date: March 2021
• Estimated Study Completion Date: July 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: VEGFR cohort: Fruquintinib

Drug: Fruquintinib in Combination with Sintilimab; Cohort A: Fruquintinib 3 mg QD, oral dosing, 3 weeks on/1 weeks off+Sintilimab 200mg Q4W, intravenous dosing. Cohort B: Fruquintinib 4 mg QD, oral dosing, 3 weeks on/1 weeks off+Sintilimab 200mg Q4W, intravenous dosing CohortC: Fruquintinib 5 mg QD, oral dosing, 2weeks on/1 weeks off+ Sintilimab 200mg Q3W, intravenous dosing CohortE: Fruquintinib 3 mg QD, continuous，oral dosing, + sinitilimab 200mg Q3W, intravenous dosing Patients will be treated until disease progression, death, unacceptable toxicity, loss of follow-up, withdrawal of consent or other conditions meet the end of treatment criteria.

Outcome Measures

Primary Outcome Measures :

1. Safety outcome evaluation - Dose Limited Toxicity (DLT), Maximum Tolerated Dose (MTD). [ Time Frame: From Cycle 1 (each cycle is 28 days) Day 1 to Cycle1 (each cycle is 28 days) Day 28 ]
   Safety in the first 28-Day of Study Treatment. Observe the possibly occurs Dose Limited Toxicity (DLT), Maximum Tolerated Dose (MTD), to confirm the Recommended Phase 2 Dose (RP2D).
2. Safety outcome evaluation - incidence, severity and outcomes of AEs (Adverse Event) [ Time Frame: From first dose to 30 days post the last dose ]
   Safety and tolerance evaluated by incidence, severity and outcomes of AEs
3. Efficacy outcome evaluation - Objective response rate [ Time Frame: Every 8 weeks since Cycle1 (each cycle is 28 days) Day 1, until disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent (assessed up to 12 months) ]
   Objective response rate (ORR),
4. Efficacy outcome evaluation - Disease control rate [ Time Frame: Every 8 weeks since Cycle 1(each cycle is 28 days) Day 1, until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months) ]
   Disease control rate (DCR),
5. Efficacy outcome evaluation - Progression free survival [ Time Frame: From Cycle 1(each cycle is 28 days) Day 1 to disease progression or death or new anti-cancer therapy or loss of follow-up or withdrawal of consent(assessed up to 12 months). ]
   Progression free survival (PFS),
6. Efficacy outcome evaluation - Overall survival [ Time Frame: From Cycle 1(each cycle is 28 days) Day1 to death or loss of follow-up or withdrawal of consent(assessed up to 12 months) ]
   Overall survival (OS)

Secondary Outcome Measures :

1. Immunogenicity Assessments for Anti-drug Antibody(ADA) [ Time Frame: From Cycle 1, 2, 4, 6, 8, 12 (each cycle is 28 days) and the safety visit for Sintilimab until disease progression or death or new anti-cancer therapy or withdrawal of consent(assessed up to 12 months) ]
   Immunogenicity Assessments for Anti-drug Antibody(ADA)
2. Pharmacokinetics Assessments for Peak Plasma Concentration (Cmax) [ Time Frame: From Cycle 1 (each cycle is 28 days) for Fruquintinib and Cycle 1, 2, 3 and 4 for Sintilimab ]
   Pharmacokinetics Assessments for Peak Plasma Concentration (Cmax)
3. Pharmacokinetics Assessments for Minimum Plasma Concentration (Cmin) [ Time Frame: From Cycle 1 (each cycle is 28 days) for Fruquintinib and Cycle 1, 2, 3 and 4 for Sintilimab ]
   Pharmacokinetics Assessments for Minimum Plasma Concentration (Cmin)
4. Pharmacokinetics Assessments for peak time (Tmax) [ Time Frame: From Cycle 1 (each cycle is 28 days) for Fruquintinib and Cycle 1, 2, 3 and 4 for Sintilimab ]
   Pharmacokinetics Assessments for peak time (Tmax)
5. Pharmacokinetics Assessments for half-life (T1/2) [ Time Frame: From Cycle 1 (each cycle is 28 days) for Fruquintinib and Cycle 1, 2, 3 and 4 for Sintilimab ]
   Pharmacokinetics Assessments for half-life (T1/2)
6. Pharmacokinetics Assessments for Assessments for Area under the plasma concentration versus time curve (AUC0-t, AUC0-∞) [ Time Frame: From Cycle 1 (each cycle is 28 days) for Fruquintinib and Cycle 1, 2, 3 and 4 for Sintilimab ]
   Pharmacokinetics Assessments for Assessments for Area under the plasma concentration versus time curve (AUC0-t, AUC0-∞)
7. Pharmacokinetics Assessments for Apparent Clearance (CL/F) [ Time Frame: From Cycle 1 (each cycle is 28 days) for Fruquintinib and Cycle 1, 2, 3 and 4 for Sintilimab ]
   Pharmacokinetics Assessments for Apparent Clearance (CL/F)
8. Pharmacokinetics Assessments for apparent volume of distribution (Vz/F) [ Time Frame: From Cycle 1 (each cycle is 28 days) for Fruquintinib and Cycle 1, 2, 3 and 4 for Sintilimab ]
   Pharmacokinetics Assessments for apparent volume of distribution (Vz/F)

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Signed informed consent;
2. 18-75 years old; BMI≥18.5;
3. Dose-escalation Phase: Histological or cytological diagnosed unresectable or metastatic advanced solid tumor (including hepatic cell cancer, ovarian cancer, endometrial cancer, thymic cancer, NSCLC and renal cancer); Expansion Phase: Histological or cytological diagnosed unresectable or metastatic advanced hepatic cell cancer, renal cancer, endometrial cancer, gastrointestinal tumor;
4. Subjects in expansion phase need to provide tissue specimen for the test of MSI or dMMR;

5. Requirements for previous anti-tumor system therapy:

   • Dose escalation stage: patients who have failed standard treatment (disease progression after treatment or intolerable side effects of treatment), no standard treatment method or unable to receive standard treatment

   • Patients enrolled in the study expansion phase are required to receive a standard treatment after disease progression, or toxicity is intolerable, or unable to receive standard treatment. The standard treatment requirements for patients with hepatocellular carcinoma, renal cell carcinoma, endometrial cancer and gastrointestinal tumors (gastric adenocarcinoma, gastroesophageal junction adenocarcinoma and colorectal adenocarcinoma) are as follows:

     • Patients with hepatocellular carcinoma have received a molecular targeted therapy (sorafenib or lenvatinib) or/and systemic chemotherapy (arsenite monotherapy or oxaliplatin-based combination drugs);
     • Patients with renal cell carcinoma have received a standard systemic anti-tumor treatment (sunitinib, sorafenib, pezopanib, axitinib, carbotinib, bevacizumab combined with IFN-α , Temsirolimus, interleukin-2 or IFN-α);
     • Patients with endometrial cancer have received a systemic anti-tumor therapy (except hormone therapy);
     • Patients with gastric adenocarcinoma and gastroesophageal junction adenocarcinoma have previously failed standard chemotherapy;
     • Patients with colorectal adenocarcinoma have previously received fluorouracil + leucovorin + platinum or irinotecan ± cetuximab or bevacizumab combination therapy.
6. ECOG (Eastern Cooperative Oncology Group) performance status of 0-1;
7. Child-Pugh score of A (< 7) for hepatic cell cancer;
8. Measurable lesions per the response evaluation criteria (RECIST 1.1) ，patients with gastric cancer require measurable lesions outside the stomach (Patients with only evaluable lesions are eligible for dose escalation stage); If the patient had regional therapy on the only lesion she/he has, it must have imaging evidence confirming disease progression after the regional therapy;

9. The test value for bone marrow, liver and renal function evaluation within 7 days prior to first dosing should meet the requirements below:

   • absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100 x 109/L（platelet of HCC patients ≥ 80 × 109 / L ） and hemoglobin ≥ 9.0 g/dL;
   • TBIL ≤ 1.5 × ULN;
   • ALT and/or AST ≤ 1.5 × ULN, or ≤ 3 × ULN for subjects with liver metastasis/ hepatic cell cancer;
   • Albumin ≥ 28g/L；
   • Creatinine ≤ 1.5 × ULN or creatinine clearance ≥50 mL/min;
   • Proteinuria <2+ by urinalysis; if Proteinuria ≥2+, proteinuria #1g by 24-hours urinary protein test is required;
   • INR ≤ 1.5 and APTT ≤ 1.5 × ULN;
10. Life expectancy of more than 12 weeks;
11. Negative of blood pregnancy test within 7 days prior to first dosing for fertile female patients. Fertile female and male patients agree to use effective contraceptive methods during the study and within 6 months post to the last dose, such as double barrier contraception, condoms, oral or injection contraceptives, intrauterine devices, abstinence, etc. All female patients will be considered fertile unless the female patient has natural menopause or has undergone artificial menopause or sterilization (hysterectomy, bilateral appendage resection);

Exclusion Criteria:

1. The adverse events due to previous anti-tumor therapy has not recovered to ≤ CTCAE Grade 1, except alopecia and peripheral neurotoxicity with ≤ CTCAE grade 2 caused by platinum chemotherapy;
2. Suffering with other malignant tumors within 5 years prior to screening (expect cured basal cell carcinoma or squamous carcinoma at skin, cervical carcinoma in situ) only for patients at dose expansion stage;
3. Fibrolamellar hepatocellular carcinoma or sarcomatoid hepatocellular carcinoma or a component of the above pathological types (HCC)，or gastric squamous cell carcinoma or gastric adenosquamous carcinoma confirmed by histology diagnosis
4. Central nervous system (CNS) metastasis in previous or screening;
5. Systematic anti-tumor therapy with approved or investigational drugs within 4 weeks prior to first dosing, including but not limited to: chemotherapy (A 2-week wash-out period required for oral fluorouracil), endocrine therapy, and bio-immunotherapy, targeted therapy (A 2-week or 5-half-lives washout period for small molecule target therapy) and traditional Chinese medicine (limited to the traditional Chinese medicine with clear indication for anti-tumor; a 1-week wash-out period required prior to first dosing);
6. Radical radiotherapy (more than 25% bone marrow involved) within 4 weeks prior to first dosing;
7. Brachytherapy (such as radioactive beads implantation) within 60 days prior to first dosing;
8. Any therapy with anti-PD-1, or anti-PD-L1/l2 antibodies or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) antibody (or any other antibody acting on T cell costimulatory or checkpoint pathway) or fruquintinib treatment in previous;
9. Steroids (more than 10 mg/day prednisone or other equivalent hormones) or other immunosuppressive agents for systemic therapy within 4 weeks prior to first dosing, except nasal spray, inhaled or other topical use of steroid (i.e. no more than 10mg/day prednisone or equivalent doses of other corticosteroids);
10. History of any active autoimmune disease or autoimmune disease, including but not limited to interstitial pneumonia, uveitis, inflammatory bowel disease, hepatitis, pituitary inflammation, vasculitis, systemic lupus erythematosus, etc. (except patients with hypothyroidism that can be controlled only by hormone replacement therapy and patients with type I diabetes who only need insulin replacement therapy);
11. Any live or attenuated live vaccine within 4 weeks prior to first dosing or planned for the duration of the study;
12. Major surgeries within 60 days prior to first dosing;
13. Any surgery or invasive treatment (except puncture biopsy, intravenous catheterization), or unhealed wounds, ulcers, fractures within 4 weeks prior to first dosing;
14. Uncontrollable malignant pleural effusion, ascites or pericardial effusion (defined as ineffectively controlled by diuresis or puncture drainage judged by investigators);
15. Drug uncontrollable hypertension, defined as systolic blood pressure ≥ 140 mmHg and / or diastolic blood pressure ≥ 90 mmHg;
16. Any disease or condition affecting drug absorption, or inability to take the investigational drug orally;
17. CYP3A4 inducers or inhibitors, P-gp or BCRP (Breast Cancer Resistant Protein) substrates were taken within 2 weeks or less than 5 half-lives (whichever was longer) prior to first dosing
18. The patients have active ulcer of stomach and duodenum, ulcerative colitis and other digestive tract diseases or unresectable tumors with active bleeding, or other conditions that may cause gastrointestinal bleeding and perforation, as judged by investigators; or the existence of gastrointestinal perforation or gastrointestinal fistula uncured post to previous surgical treatment;
19. Patients with evidence or history of propensity to hemorrhage within 2 months prior to first dosing, regardless of severity(such as melena, hematemesis, hemoptysis, bloody stools）；
20. High risk of bleeding at screening due to tumor invasion into major vessels, such as pulmonary artery, the superior vena cava, or the inferior vena cava, as determined by investigators;
21. Arterial thrombosis or deep venous thrombosis within 6 months prior to first dosing, or thromboembolic events (including stroke and/or transient ischemic attack) within 12 months prior to first dosing;or due to implanted venous infusion pump or catheter-derived thrombosis ，or those with superficial venous thrombosis;
22. Cardiovascular diseases of significant clinical significance, including, but not limited to acute myocardial infarction, severe/unstable angina pectoris or coronary artery bypass grafting within 6 months prior to first dosing, congestive heart failure with New York Heart Association (NYHA) grade ≥ 2; Left ventricular ejection fraction (LVEF) < 50%;
23. Clinically significant abnormal electrolyte abnormality as judged by investigators;
24. Active infection or fever of unknown origin prior to first dosing (body temperature > 38.5 oC) at screening;
25. Patients with active pulmonary tuberculosis receiving anti-tuberculosis treatment or with anti-tuberculosis treatment within 1 year prior to first dosing;
26. History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonia, severe impairment of the lung function, etc., which may interfere with the detection and treatment of suspected drug-related lung toxicity, except radiation pneumonitis in the radiation treatment area;
27. Confirmed human immunodeficiency virus (HIV) infection;
28. Clinically significant liver disease, including active viral hepatitis [HBsAg and/or HbcAb is positive and HBV (hepatitis B virus) DNA > 10000 copies/ mL or > 2000 IU/mL; HCV (hepatitis C virus) antibody positive and HCV RNA positive], or other active hepatitis, clinically significant moderate to severe cirrhosis;
29. Any unapproved drug taken within 4 weeks prior to first dosing.
30. Female patients with pregnancy or breastfeeding;
31. History of allergies to any ingredient of Sintilimab or Fruquintinib or significant allergy history to any mono-antibody;
32. Any condition by which investigators judge patients not suitable to participate in this study

Contacts and Locations

Contacts

Contact: Panfeng Tan, MD; +86 21 20671828 ext 5828; panfengt@hmplglobal.com

Contact: Yunfei Xia; +86 21 20671828 ext 5818; yunfeix@hmplglobal.com

Locations

China, Shanghai

Shanghai East Hospital; Recruiting

Shanghai, Shanghai, China, 201203

Contact: Jing Li, Doctor +86 13761222111 lijin@csco.org.cn

Sponsors and Collaborators

Hutchison Medipharma Limited

Investigators

• Principal Investigator: Jin Li; Shanghai East Hospital

More Information

• Responsible Party: Hutchison Medipharma Limited
• ClinicalTrials.gov Identifier: NCT03903705
• Other Study ID Numbers: 2018-013-00CH3
• First Posted: April 4, 2019
• Last Update Posted: September 14, 2020
• Last Verified: March 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Hutchison Medipharma Limited:

Fruquintinib; Sintilimab; VEGFR; PD-1; Solid Tumor

Additional relevant MeSH terms:

Neoplasms