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Study to Evaluate Apatinib (Also Known as Rivoceranib) Plus Nivolumab in Patients With Unresectable or Metastatic Cancer

NCT03396211

Description:

This is an open-labeled, single-center, Phase I study to evaluate the safety, tolerability, and efficacy of apatinib (also known as rivoceranib) with nivolumab treatment in patients with unresectable or metastatic cancer. Approximately 12-18 subjects in Phase I dose escalation phase and up to 20 additional subjects in Part II expansion phase. Total study duration will be approximately 18 months: 12 months of recruitment plus 6 months of treatment.

Related Conditions:
  • Alveolar Soft Part Sarcoma
  • Angiosarcoma
  • Breast Carcinoma
  • Gastric Adenocarcinoma
  • Leiomyosarcoma
  • Malignant Solid Tumor
  • Melanoma
  • Non-Small Cell Lung Carcinoma
  • Renal Cell Carcinoma
  • Synovial Sarcoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study to Evaluate Apatinib (Also Known as Rivoceranib) Plus Nivolumab in Patients With Unresectable or Metastatic Cancer
  • Official Title: An Open-Labeled, Phase I Study to Evaluate the Safety and Tolerability of Apatinib With Nivolumab in Patients With Unresectable or Metastatic Cancer

Clinical Trial IDs

  • ORG STUDY ID: LSK-AM107
  • NCT ID: NCT03396211

Conditions

  • Cancer

Interventions

DrugSynonymsArms
Apatinib (also known as rivoceranib)Apatinib (also known as rivoceranib) with Nivolumab
NivolumabOpdivoApatinib (also known as rivoceranib) with Nivolumab

Purpose

This is an open-labeled, single-center, Phase I study to evaluate the safety, tolerability, and efficacy of apatinib (also known as rivoceranib) with nivolumab treatment in patients with unresectable or metastatic cancer. Approximately 12-18 subjects in Phase I dose escalation phase and up to 20 additional subjects in Part II expansion phase. Total study duration will be approximately 18 months: 12 months of recruitment plus 6 months of treatment.

Detailed Description

      Primary objectives:

        -  To evaluate the safety and tolerability of apatinib with nivolumab in patients with
           unresectable or metastatic cancer

        -  To assess efficacy by objective response rate (ORR), best overall response (BOR), time
           to response (TTR), and duration of response (DoR) per RECIST v1.1 and/or iRECIST

        -  To assess disease control rate (DCR), and duration of disease control (DDC) by RECIST
           v1.1, and/or iRECIST

      Secondary objectives:

      • To evaluate the efficacy of apatinib with nivolumab in patients with unresectable or
      metastatic cancer as measured by:

        -  Overall survival (OS)

        -  Progression-free survival (PFS)

        -  Event-free survival (EFS)

      Exploratory objectives:

        -  Tumor mutational burden and mutations at baseline and at the time of progression

        -  Changes in serum cytokines pursuant to treatment response

        -  Changes in PBMC subsets and MDSC populations as determined by flow cytometry
    

Trial Arms

NameTypeDescriptionInterventions
Apatinib (also known as rivoceranib) with NivolumabExperimentalOral daily doses of apatinib (as its mesylate salt) with a fixed dose of nivolumab given intravenously every 2 weeks
  • Apatinib (also known as rivoceranib)
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Male or female at least 18 years old or older.

          2. Documented primary diagnosis of histologic- or cytologic-confirmed solid tumor cancer
             inclusive of gastric adenocarcinoma, renal cell carcinoma, melanoma, non-small cell
             lung cancer (NSCLC), breast cancer, angiosarcoma, leiomyosarcoma, synovial sarcoma,
             and alveolar soft part sarcoma or other solid tumor for which anti-VEGFR-2 targeted
             therapy could be applicable.

          3. Locally advanced unresectable or metastatic disease.

          4. Nivolumab treatment naive and able to begin nivolumab treatment concurrently with
             initiation of apatinib or have received at least three doses of nivolumab treatment
             and are continuing nivolumab therapy.

          5. One or more measurable lesions per RECIST v1.1.

          6. Subjects who have adequate bone-marrow, renal and liver function including:

               1. Hematologic: absolute neutrophil count ≥ 1,500/mm3, platelets≥ 100,000/mm3,
                  hemoglobin ≥ 9.0 g/dL (blood transfusion to meet the inclusion criteria within 2
                  weeks is not allowed).

               2. Renal: serum creatinine < 1.5× ULN; urinary protein should be< 2+ on dipstick or
                  routine urinalysis. If urine dipstick or routine analysis indicates proteinuria ≥
                  2+, then a 24-hour urine or urine protein/creatinine ratio must be collected and
                  must demonstrate <2 g of protein in 24 hours to allow participation in the study.

               3. Hepatic: serum bilirubin < 1.5× ULN, AST and ALT ≤ 3.0× ULN(≤ 4.0× ULN, if with
                  liver metastases).

               4. Blood coagulation tests: PTT and INR ≤ 1.5× ULN and ≤ 1.5×ULN, respectively.

          7. Eastern Cooperative Oncology Group (ECOG) performance status are evaluated to be ≤ 1
             (Subjects with ECOG performance status of 2 may be enrolled only with advance review
             and written approval by the medical monitor.)

          8. Expected survival of ≥ 12 weeks, in the judgement of the investigator.

          9. Ability to swallow the study drug tablets.

         10. Female subjects of child-bearing potential must have a negative serum or urine
             pregnancy test at the Screening Visit. Females must be surgically sterile,
             postmenopausal for at least 1 year prior to Screening Visit (no other medical cause
             involved) or must be using an acceptable method of birth control effectively.
             Acceptable methods of birth control include hormone contraceptives [oral, non-oral, or
             implants], contraception double barrier methods, intrauterine contraceptive device or
             systems that are approved or certified by the FDA.

         11. Ability and willingness to comply with the study protocol for the duration of the
             study and with follow-up procedures, including signature of the IRB-approved informed
             consent form.

        Exclusion Criteria:

          1. History of another malignancy within 2 years prior to enrollment, unless it does not
             pose a significant risk to life expectancy as per the investigator.

          2. CNS metastases as shown by radiology records or clinical evidence of symptomatic CNS
             involvement in the last 3 months prior to enrollment.Subjects are eligible if
             metastases have been treated and have returned to neurologic baseline or are
             neurologically stable (except for residual signs or symptoms related to the CNS
             treatment).

          3. Cytotoxic chemotherapy, surgery, radiotherapy or other targeted therapies and
             checkpoint inhibitors (excluding nivolumab if not nivolumab treatment naive) within 3
             weeks (4 weeks in cases of ramucirumab,mitomycin C, nitrosourea, lomustine; 1 week in
             case of biopsy) prior to enrollment (adjuvant radiotherapy given to local area for
             non-curative symptom relief is allowed until 2 weeks before enrollment).

          4. Any other therapies including biological and approved therapies within 3 half-lives or
             3 weeks whichever is longer and have not recovered from all toxicities from the
             treatment.

          5. Therapy with clinically significant systemic anticoagulant or anti thrombotic agents
             within 7 days prior to enrollment that may prevent blood clotting and, in the
             investigator's opinion, could place the subject at risk. Maximum dose of 325 mg/day of
             aspirin is allowed.

          6. History of bleeding diathesis or clinically significant bleeding within 14days prior
             to enrollment.

          7. History of clinically significant thrombosis (bleeding or clotting disorder)within the
             past 3 months prior to enrollment that, in the investigator's opinion, may place the
             subject at risk of side effects from anti-angiogenesis products.

          8. History of gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer
             disease within the past 3 months prior to enrollment that, in the investigator's
             opinion, may place the subject at risk of side effects from anti-angiogenesis
             products.

          9. Myocardial infarction or an unstable angina pectoris within 3 months prior to
             enrollment.

         10. Prior major surgery or fracture within 3 weeks prior to enrollment or presence of any
             non-healing wound (procedures such as catheter placement are not considered to be
             major).

         11. Participation in any other interventional clinical trial, within 4 weeks prior to
             enrollment or while participating in this study.

         12. Previous treatment with apatinib.

         13. Hypersensitivity to apatinib or components of its formulation.

         14. History of uncontrolled hypertension ([HTN], blood pressure ≥ 140/90mmHg and change in
             anti hypertensive medication within 7 days prior to enrollment) that is not well
             managed by medication and the risk of which may be precipitated by VEGF inhibitor
             therapy.

         15. History of severe adverse events including uncontrolled HTN or other common
             anti-angiogenesis class drug effects that were related to ramucirumab or bevacizumab
             discontinuation and/or may indicate a higher risk to the safety of the subject if
             provided further anti-angiogenesis treatment, in the investigator's opinion.

         16. History of symptomatic congestive heart failure (New York Heart Association III-IV),
             symptomatic or poorly controlled cardiac arrhythmia, complete left bundle branch
             block, bifascicular block, or any clinically significant ST segment and/or T-wave
             abnormalities, QTcF>450 msec for males or QTcF > 470 msec for females prior to
             enrollment.

         17. Concomitant treatment with strong inhibitors or inducers of CYP3A4,CYP2C9, and
             CYP2C19.

         18. History of drug or alcohol abuse within past 5 years.

         19. Known history of human immunodeficiency virus (HIV) infection or known acquired
             immunodeficiency syndrome (AIDS).

         20. Known history of positive tests for hepatitis B virus surface antigen (HBVsAg) or
             hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection.

         21. Pregnant or breast-feeding females.

         22. Active bacterial infections.

         23. Presence of substance abuse, medical, psychological, or social illness(es)that, in the
             judgement of the investigator, may interfere with the subject's participation or
             safety, or which may impact the objectives of the study.

         24. History of clinically significant glomerulonephritis, biopsy-proven tubulointerstitial
             nephritis, crystal nephropathy, or other renal insufficiencies.

         25. Gastrointestinal malabsorption, or any other condition that in the opinion of the
             investigator might affect the absorption of the study drug.

         26. Grade 2 or greater toxicity from ongoing nivolumab treatment and irAE including
             colitis and pneumonitis, if not nivolumab treatment naive.

         27. Active autoimmune disease or a history of known autoimmune disease.

         28. History of drug-induced interstitial pneumonitis or severe hypersensitivity to other
             antibody therapies.

         29. Known or underlying medical condition (e.g., a condition associated with diarrhea or
             acute diverticulitis) that, in the investigator's opinion, would make the
             administration of study drug hazardous to the subject or obscure the interpretation of
             toxicity determination or adverse events.

         30. Other conditions that, in the judgement of the investigator, contraindicate study
             participation.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of apatinib administered orally in combination with nivolumab
Time Frame:28 days (1 cycle (28days) of apatinib; 2 doses of nivolumab (q 2wks))
Safety Issue:
Description:A traditional escalation rule, also known as "3 + 3" rule, will be used for this study. Subjects are treated in sequential groups of 3 with each receiving the same dose. If none of the 3 subjects experience a Dose Limiting Toxicity (DLT) within Cycle 1, the next group of 3 subjects receives the next higher dose. If 1 of the 3 subjects treated at that dose level experience a DLT within Cycle 1, the group will expand to 6 subjects treated at the same dose level. If no additional DLT occurs, the next dosing group will begin. If two or more subjects experience a DLT at the dose level within cycle 1, then escalation stops at that level and the prior dose level will be considered the MTD. The highest dose with only one DLT in 6 subjects or no DLTs with 3 subjects will be considered the MTD.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:Every other cycle (approximately at 8 weeks after initiation of treatment and every 8 weeks thereafter) until end of study (approximately 1 year)
Safety Issue:
Description:OS is the time from subject enrollment until death from any cause and will be summarized using the Kaplan-Meier method. Median OS, along with 95% CI will be constructed based on a log-log transformed CI for the survivor function. Subjects without documentation of death will be censored on the last date the participant was known to be alive.
Measure:Event Free Survival (EFS)
Time Frame:Every other cycle (approximately at 8 weeks after initiation of treatment and every 8 weeks thereafter) until end of study (approximately 1 year)
Safety Issue:
Description:EFS is defined as time from enrollment to a > 20% increase tumor size from baseline by RECIST v1.1, development of distant metastatic disease, or death. Tumor disease progression is defined as the sum of the longest diameter(s) of target tumor(s) increased by at least 20% from the baseline acquired at enrollment. The EFS distribution will be summarized using the Kaplan-Meier method.
Measure:Progression Free Survival (PFS)
Time Frame:Every other cycle (approximately at 8 weeks after initiation of treatment and every 8 weeks thereafter) until end of study (approximately 1 year)
Safety Issue:
Description:PFS is the time from start of apatinib treatment to either radiological progression or death, whichever occurs first. Subjects alive and free of progression at the end of study are censored. Median PFS, along with the 95% CI will be constructed based on a log-log transformed CI for the survivor function. Subjects without a reported progression will be considered to have progressed on the date of their death if no subsequent anticancer therapy initiated. Subjects who did no progress or die will be censored on the date of the last tumor assessment. Subjects who did not have any on-study tumor assessments and did not die will be censored on the first dosing date. Subjects who started subsequent anti-cancer therapy and without a prior reported progression will be censored at the last tumor assessment prior to initiation of the subsequent therapy.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:LSK BioPartners Inc.

Trial Keywords

  • Metastatic
  • Unresectable

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