Safety, Tolerability and Efficacy Profile of Rivoceranib With Paclitaxel in Advanced GC or GEJ Cancer.

• ClinicalTrials.gov Identifier: NCT03707028
• Recruitment Status: Recruiting
• First Posted: October 16, 2018
• Last Update Posted: September 5, 2021
• Sponsor: Elevar Therapeutics
• Information provided by (Responsible Party): Elevar Therapeutics

Study Description

Brief Summary:

This is an open-label, single-center, single-arm, dose escalation and dose expansion Phase I/IIa study designed to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), and the safety and tolerability profile along with preliminary signs of efficacy of rivoceranib in combination with paclitaxel as a second-line therapy in advanced, recurrent and/or metastatic gastric or gastroesophageal junction cancer. This study will also characterize the pharmacokinetic (PK) parameters of rivoceranib and paclitaxel when given in combination.

Condition or disease	Intervention/treatment	Phase
Gastric Cancer; Gastroesophageal Junction Adenocarcinoma	Drug: Rivoceranib; Drug: Paclitaxel	Phase 1; Phase 2

Detailed Description:

Primary Phase I Objectives

• To determine the maximum tolerated dose and recommended Phase 2 dose of rivoceranib in combination with paclitaxel.

Primary Phase II Objectives

• To determine clinical activity of the combination of rivoceranib and paclitaxel

Secondary Phase I Objectives

• To evaluate the pharmacokinetics (PK) of rivoceranib and paclitaxel when given in combination.
• To assess the efficacy of rivoceranib in combination with paclitaxel.

Secondary Phase II Objectives

• To assess the efficacy of rivoceranib in combination with paclitaxel.
• To assess the safety and tolerability of rivoceranib in combination with paclitaxel.
• To assess the PK of rivoceranib and paclitaxel when given in combination.

Exploratory Phase I/II Objectives

• To evaluate tumor expression of proteins related to paclitaxel resistance at prior to first-line chemotherapy and at prior to this study.
• To evaluate the correlation between response to treatment and tumor expression of proteins related to paclitaxel resistance.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/IIa Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of Rivoceranib in Combination With Paclitaxel in Advanced Gastric or Gastroesophageal Junction Cancer.
• Actual Study Start Date: October 1, 2018
• Estimated Primary Completion Date: October 8, 2021
• Estimated Study Completion Date: January 31, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Rivoceranib (apatinib) with Paclitaxel; Oral daily doses of rivoceranib (as its mesylate salt) with a fixed dose of paclitaxel given intravenously on day 1, day 8, and day 15.	Drug: Rivoceranib; Oral daily doses of rivoceranib (as its mesylate salt); Other Name: apatinib; Drug: Paclitaxel; Fixed dose of paclitaxel given intravenously on day 1, day 8, and day 15; Other Name: Taxol

Outcome Measures

Primary Outcome Measures :

1. Phase I: Maximum tolerated dose (MTD) of rivoceranib administered orally in combination with paclitaxel [ Time Frame: 1 cycle (28 days) ]
   A dose escalation rule will be used for this study.
2. Phase II: Objective Response Rate (ORR) [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
   ORR is the percentage of patients with a reduction in tumor burden beyond a set threshold using RECIST 1.1 criteria for response.

Secondary Outcome Measures :

1. Phase I: Cmax [ Time Frame: Day 1 & 15 of Cycle 1 (each cycle is 28 days) ]
   Maximum observed concentration
2. Phase I: tmax [ Time Frame: Day 1 & 15 of Cycle 1 (each cycle is 28 days) ]
   Time to maximum observed concentration
3. Phase I: AUC0-t [ Time Frame: Day 1 & 15 of Cycle 1 (each cycle is 28 days) ]
   Area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration
4. Phase I: AUC0-∞ [ Time Frame: Day 1 & 15 of Cycle 1 (each cycle is 28 days) ]
   Area under the plasma concentration-time curve from time 0 extrapolated to infinity
5. Phase I: t1/2 [ Time Frame: Day 1 & 15 of Cycle 1 (each cycle is 28 days) ]
   Terminal half-life
6. Phase I: CL/F [ Time Frame: Day 1 & 15 of Cycle 1 (each cycle is 28 days) ]
   Apparent oral plasma clearance
7. Phase I: Vz/F [ Time Frame: Day 1 & 15 of Cycle 1 (each cycle is 28 days) ]
   Apparent volume of distribution
8. Phase I: λz [ Time Frame: Day 1 & 15 of Cycle 1 (each cycle is 28 days) ]
   Terminal rate constant
9. Phase I: ORR [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
   Objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1)
10. Phase I: PFS [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
    Progression-free survival (PFS). Defined as time from first dose of study drug (Cycle 1 Day 1) to the time of first documented disease progression or death due to any cause
11. Phase I: OS [ Time Frame: Ongoing assessment from enrollment until end of study, up to approximately 24 months ]
    Overall survival (OS). Overall survival is the time from first dose of study drug (Cycle 1 Day 1) to the time of death from any cause
12. Phase I: DCR [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
    Disease control rate (DCR) based on tumor response and stabilization over at least 12 weeks
13. Phase I: Duration of response [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
    Duration of response. Defined as the time from first documentation of (complete response or partial response) to the first documentation of progression
14. Phase II: PFS [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
    Progression-free survival (PFS). Defined as time from first dose of study drug (Cycle 1 Day 1) to the time of first documented disease progression or death due to any cause
15. Phase II: OS [ Time Frame: Ongoing assessment from enrollment until end of study, up to approximately 24 months ]
    Overall survival (OS). Overall survival is the time from first dose of study drug (Cycle 1 Day 1) to the time of death from any cause
16. Phase II: DCR [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
    Disease control rate (DCR) based on tumor response and stabilization over at least 12 weeks
17. Phase II: Duration of response [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
    Duration of response. Defined as the time from first documentation of (complete response or partial response) to the first documentation of progression
18. Phase II: AEs and SAEs [ Time Frame: Ongoing assessment from enrollment until end of study, approximately 24 months ]
    Adverse Events and Serious Adverse Events

Other Outcome Measures:

1. Phase II Exploratory: Expression of paclitaxel resistance-related proteins [ Time Frame: Prior to study participation and optionally at end of treatment, approximately 24 months ]
   Tumor expression of P-glycoprotein and beta-tubulin proteins by immunohistochemistry and/or mass spectrometry
2. Phase II Exploratory: PFS [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
   PFS correlated against expression of paclitaxel resistance related protein
3. Phase II Exploratory: ORR [ Time Frame: Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months ]
   Response rate correlated against expression of paclitaxel resistance related protein

Eligibility Criteria

• Ages Eligible for Study: 19 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria

Patients are eligible to be included in the study only if all the following criteria apply:

1. Patients must be ≥19 year old years of age, at the time of signing the informed consent.
2. Patients with documented locally advanced unresectable or metastatic gastric or gastroesophageal junction cancer refractory to or relapsing after first line platinum and fluoropyrimidine containing chemotherapy (with or without trastuzumab) with an indication for therapy with paclitaxel and an antiangiogenic agent. If disease progression occurs during or within 6 months after completion of any adjuvant chemotherapy, this therapy is considered a first-line chemotherapy for subject eligibility.
3. Patients who have provided tumor tissue prior to initiation of first-line therapy and have provided or can provide tumor tissue prior to screening in this study. This will be optional for Phase I patients. Tumor tissue must not have been irradiated.
4. Patients who have at least 1 measurable lesion as defined by RECIST v1.1. This will be optional for Phase I patients.

5. Adequate bone marrow, renal and liver function evidenced by:

   1. Hematologic: Absolute neutrophil count of ≥1,500/mm³, platelet count of ≥ 1,00,000/mm³, and hemoglobin of ≥9.0 g/dL. Transfusion of platelets or red blood cells to meet the inclusion criteria within 2 weeks of screening is not allowed.
   2. Adequate renal function defined as meeting any 1 of the following criteria:

   i. Serum creatinine <1.5 × upper limit of normal (ULN). ii. Creatinine clearance based on the Cockcroft-Gault estimate ≥50 mL/min or creatinine clearance based on urine collection (12 or 24 hours) ≥50 mL/min.

   iii. In addition, 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.

   c) Hepatic: Serum bilirubin <1.5 × ULN, aspartate and alanine aminotransferase ≤3.0 × ULN (≤5.0 × UNL, if with liver metastases). If liver and/or bone metastases alkaline phosphatase ≤5 × ULN.

6. Blood coagulation tests: Prothrombin time and international normalized ratio ≤1.5 × ULN.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
8. Estimated life expectancy of at least 12 weeks.
9. Ability to swallow the study drug without chewing, breaking, crushing, opening or otherwise altering the product formulation. If vomiting occurs, the dose will not be replaced. Antiemetics must be used at efficacious doses.
10. No major gastrointestinal disease (e.g., chronic diarrheal disease) or intestinal surgery that can jeopardize drug absorption.

11. Contraception and pregnancy:

    1. Male patients:

       A male patient must agree to use contraception as detailed in Appendix 6 of this protocol during the treatment period and for at least 95 days after the last dose of study drug and refrain from donating sperm during this period.

    2. Female patients:

    A female patient is eligible to participate if she has a negative serum pregnancy test at screening (see Appendix 6), is not breastfeeding, and at least 1 of the following conditions applies:

    i) Not a woman of childbearing potential as defined in Appendix 6. OR ii) A woman of childbearing potential who agrees to follow the contraceptive guidance in Appendix 6 during the treatment period and for at least 35 days after the last dose of study treatment.

12. Ability and willingness to comply with the study protocol for the duration of the study and with follow up procedures.
13. Capable of giving signed informed consent as described in Appendix 2, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion Criteria

Patients are excluded from the study if any of the following criteria apply:

1. Prior use of taxane (paclitaxel or docetaxel) or any contraindication for therapy with paclitaxel.
2. Previous treatment with rivoceranib or any other systemic therapy with a VEGF pathway inhibitor.
3. Known hypersensitivity to rivoceranib or any component of its formulation or history of severe AEs including uncontrolled hypertension or other common anti-angiogenesis drug class effects during prior exposure to VEGF inhibitors.
4. Any unresolved toxicity Grade >1 (except alopecia) from previous anticancer therapy (including radiotherapy).

5. Has history of another malignancy within 2 years prior to screening. Patients with the following are eligible for this study if, in the opinion of the investigator, they do not pose a significant risk to life expectancy:

   1. Bladder tumors considered superficial such as noninvasive (T1a) and carcinoma in situ (Tis).
   2. Curatively treated cervical carcinoma in situ.
   3. Thyroid papillary cancer with prior treatment.
   4. Carcinoma of the skin without melanomatous features.
   5. Prostate cancer which has been surgically or medically treated and not likely to recur within 2 years.
6. Known brain metastasis or other central nervous system metastasis that is either symptomatic or untreated. Metastases that have been treated by complete resection and/or radiotherapy demonstrating stability or improvement are not an exclusion criterion provided they are stable as shown by CT scan at least 4 weeks before screening without evidence of cerebral edema. Patients on stable dose of corticosteroids or anticonvulsants are permitted.
7. Has received prior anticancer therapy within 3 weeks before Cycle 1 Day 1. Traditional herbal remedies with anti-infective, immune stimulating or anticancer properties are not allowed from screening throughout the entire period of study participation.
8. Current or recent (within 10 days of Cycle 1 Day 1) use of full dose oral or parenteral anticoagulants or other thrombolytic agents for therapeutic (as opposed to prophylactic) purposes, clinically serious non healing wounds, or incompletely healed bone fracture. A maximum dose of 325 mg/day of aspirin is allowed.
9. Patients who had therapeutic paracentesis of ascites (>1L) within the 2 months prior to starting study treatment or who, in the opinion of the investigator, will likely need therapeutic paracentesis of ascites (>1L) within 2 months of Cycle 1 Day 1.
10. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19.
11. Active bacterial infections (including tuberculosis and syphilis) requiring systemic antibiotic therapy.
12. Known history of human immunodeficiency virus infection.
13. Active hepatitis B or C infection or chronic hepatitis B or C infection requiring treatment with antiviral therapy or prophylactic antiviral therapy; unless evidence of viral suppression has been documented and the patient will remain on appropriate antiviral therapy throughout the study.
14. Child-Pugh Stage B and C liver function impairment.
15. Pregnant or breastfeeding women. Patients unwilling to comply with birth control requirements will not be eligible.
16. History of uncontrolled hypertension (blood pressure ≥140/90 mmHg and change in antihypertensive medication within 7 days prior to screening) that is not well managed by medication and the risk of which may be precipitated by a VEGF inhibitor therapy. History of hypertensive crisis, and hypertensive encephalopathy.
17. Patients who have a known history of symptomatic congestive heart failure (New York Heart Association III to 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 screening.
18. History of bleeding diathesis or clinically significant bleeding within 14 days prior to Cycle 1 Day 1. This includes a history of gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3 months prior to Cycle 1 Day 1 that, in the investigator's opinion, may place the patient at risk of side effects from anti-angiogenesis products.
19. History of clinically significant thrombosis (bleeding or clotting disorder) within the past 3 months prior to Cycle 1 Day 1 that, in the investigator's opinion, may place the patient at risk of side effects from anti-angiogenesis products.
20. History of other significant cardiovascular diseases or vascular diseases, within the last 6 months prior to screening (e.g., myocardial infarction or unstable angina pectoris, stroke or transient ischemic attack, or significant peripheral vascular diseases) that, in the investigator's opinion, may pose a risk to the patient on VEGFR inhibitor therapy.
21. History of clinically significant glomerulonephritis, biopsy-proven tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies.
22. Psychological, familial, sociological, or geographical conditions including drug or alcohol abuse that do not permit compliance with the study participation or evaluation of the study results.

Contacts and Locations

Contacts

Contact: Jaehong Kim; +82-10-2041-4326; jhkim@elevartherapeutics.com

Locations

Korea, Republic of

Asan Medical Center; Recruiting

Seoul, Korea, Republic of, 05505

Contact: Hyejin Lee +82-2-2045-3852 her890526@amc.seoul.kr

Principal Investigator: Yoon-Koo Kang, MD, PhD

Sub-Investigator: Min-Hee Ryu, MD, PhD

Sponsors and Collaborators

Elevar Therapeutics

Investigators

• Principal Investigator: Min-Hee Ryu, Dr.; Asan Medical Center

More Information

• Responsible Party: Elevar Therapeutics
• ClinicalTrials.gov Identifier: NCT03707028
• Other Study ID Numbers: LSK-RM109
• First Posted: October 16, 2018
• Last Update Posted: September 5, 2021
• Last Verified: September 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Paclitaxel; Apatinib; Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Protein Kinase Inhibitors; Enzyme Inhibitors