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

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ClinicalTrials.gov Identifier: NCT03396211
Recruitment Status : Recruiting
First Posted : January 10, 2018
Last Update Posted : July 16, 2018
Sponsor:
Information provided by (Responsible Party):
LSK BioPartners Inc.

Brief Summary:
This is an open-labeled, single-center, Phase I study to evaluate the safety, tolerability, and efficacy of adding apatinib (also known as rivoceranib) to ongoing nivolumab treatment in patients with unresectable or metastatic cancer. Approximately 9-18 subjects in Phase I dose escalation phase and up to 12 additional subjects in Part II expansion phase. Total study duration will be approximately 12 months: 6 months of recruitment plus 6 months of treatment.

Condition or disease Intervention/treatment Phase
Cancer Drug: Apatinib (also known as rivoceranib) Drug: Nivolumab Phase 1

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This protocol contains two parts: 1) a classic 3+3 dose escalation period to evaluate the safety of apatinib (also known as rivoceranib) in combination with nivolumab, and 2) an expansion period with open-label administration of apatinib at a dose up to 700 mg qd (as 869 mg apatinib mesylate) or at the maximum tolerated dose (MTD) obtained from Part I of this study. Subjects for both Part I and Part II will be enrolled after informed consent and deemed eligible following screening procedures.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Labeled, Phase I Study to Evaluate the Safety and Tolerability of Apatinib and Nivolumab in Patients With Unresectable or Metastatic Cancer
Actual Study Start Date : December 22, 2017
Estimated Primary Completion Date : September 22, 2019
Estimated Study Completion Date : December 22, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Nivolumab

Arm Intervention/treatment
Experimental: Apatinib (also known as rivoceranib) with Nivolumab
Oral daily doses of apatinib (as its mesylate salt) with a fixed dose of nivolumab given intravenously every 2 weeks
Drug: Apatinib (also known as rivoceranib)
Oral daily doses of apatinib (as its mesylate salt)

Drug: Nivolumab
Fixed dose of nivolumab given intravenously every 2 weeks
Other Name: Opdivo




Primary Outcome Measures :
  1. 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)) ]
    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.

  2. Objective Response Rate (ORR) [ 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) ]
    ORR is the percentage of patients with a reduction in tumor burden beyond a set threshold using RECIST v1.1 and iRECIST criteria for response (i.e. PR or CR).

  3. Best Overall Response Rate (BOR) [ 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) ]
    BOR is the best response, according to RECIST v1.1 or iRECIST criteria, recorded over the duration of the study until disease progression, or recurrence.

  4. Time To Response (TTR) [ 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) ]
    TTR is the time lapsed from enrollment until documented response according to RECIST v1.1 or iRECIST criteria.

  5. Duration of Response (DoR) [ 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) ]
    DoR is the time from documented tumor response (PR or CR) until disease progression or death from any cause, whichever occurs first.

  6. Disease Control Rate (DCR) [ 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) ]
    DCR is the proportion of patients with radiologically documented stable or decreased tumor burden per RECIST v1.1 and iRECIST criteria.

  7. Duration of Disease Control (DDC) [ 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) ]
    DDC is the time from enrollment until disease progression or death from any cause, whichever occurs first.


Secondary Outcome Measures :
  1. 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) ]
    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.

  2. 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) ]
    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.

  3. 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) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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), and breast or other solid tumor for which anti-VEGFR-2 targeted therapy could be applicable.
  3. Locally advanced unresectable or metastatic disease.
  4. 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(excluding nivolumab) 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.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03396211


Contacts
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Contact: Scott Houston 8013037440 ext 220 scotthouston@lskbiopharma.com

Locations
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United States, California
Sarcoma Oncology Research Center Recruiting
Santa Monica, California, United States, 90403
Contact: Victoria Chua    310-552-9999    vchua@sarcomaoncology.com   
Principal Investigator: Sant P. Chawla, M.D.         
Sponsors and Collaborators
LSK BioPartners Inc.
Investigators
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Study Director: Scott Houston LSK BioPartners Inc.

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Responsible Party: LSK BioPartners Inc.
ClinicalTrials.gov Identifier: NCT03396211     History of Changes
Other Study ID Numbers: LSK-AM107
First Posted: January 10, 2018    Key Record Dates
Last Update Posted: July 16, 2018
Last Verified: July 2018

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

Keywords provided by LSK BioPartners Inc.:
Metastatic
Unresectable

Additional relevant MeSH terms:
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Neoplasm Metastasis
Neoplastic Processes
Neoplasms
Pathologic Processes
Nivolumab
Apatinib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action