Patient case: 57-year-old male with lung adenocarcinoma; genetic feature: KRAS (G12V), high tumor mutational burden

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

Summary: 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

Eligibility: 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.

Relevance to patient case: not relevant