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

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.

Sponsors

Lead Sponsor: Elevar Therapeutics

Source Elevar Therapeutics
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.

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.

Overall Status Recruiting
Start Date October 1, 2018
Completion Date December 2020
Primary Completion Date August 2020
Phase Phase 1/Phase 2
Study Type Interventional
Primary Outcome
Measure Time Frame
Phase I: Maximum tolerated dose (MTD) of rivoceranib administered orally in combination with paclitaxel 1 cycle (28 days)
Phase II: Objective Response Rate (ORR) Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months
Secondary Outcome
Measure Time Frame
Phase I: Cmax Day 1 & 15 of Cycle 1 (each cycle is 28 days)
Phase I: tmax Day 1 & 15 of Cycle 1 (each cycle is 28 days)
Phase I: AUC0-t Day 1 & 15 of Cycle 1 (each cycle is 28 days)
Phase I: AUC0-∞ Day 1 & 15 of Cycle 1 (each cycle is 28 days)
Phase I: t1/2 Day 1 & 15 of Cycle 1 (each cycle is 28 days)
Phase I: CL/F Day 1 & 15 of Cycle 1 (each cycle is 28 days)
Phase I: Vz/F Day 1 & 15 of Cycle 1 (each cycle is 28 days)
Phase I: λz Day 1 & 15 of Cycle 1 (each cycle is 28 days)
Phase I: ORR Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months
Phase I: PFS Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months
Phase I: OS Ongoing assessment from enrollment until end of study, up to approximately 24 months
Phase I: DCR Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months
Phase I: Duration of response Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months
Phase II: PFS Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months
Phase II: OS Ongoing assessment from enrollment until end of study, up to approximately 24 months
Phase II: DCR Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months
Phase II: Duration of response Every other cycle (each cycle is 28 days) until end of study, assessed up to 24 months
Phase II: AEs and SAEs Ongoing assessment from enrollment until end of study, approximately 24 months
Enrollment 38
Condition
Intervention

Intervention Type: Drug

Intervention Name: Rivoceranib

Description: Oral daily doses of rivoceranib (as its mesylate salt)

Arm Group Label: Rivoceranib (apatinib) with Paclitaxel

Other Name: apatinib

Intervention Type: Drug

Intervention Name: Paclitaxel

Description: Fixed dose of paclitaxel given intravenously on day 1, day 8, and day 15

Arm Group Label: Rivoceranib (apatinib) with Paclitaxel

Other Name: Taxol

Eligibility

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.

Gender: All

Minimum Age: 19 Years

Maximum Age: N/A

Healthy Volunteers: No

Overall Official
Last Name Role Affiliation
Arlo McGinn, PhD Study Director Elevar Therapeutics
Overall Contact

Last Name: Jaehong Kim

Phone: +82-10-2041-4326

Email: [email protected]

Location
Facility: Status: Contact: Investigator: Asan Medical Center Hyejin Lee +82-2-2045-3852 [email protected] Yoon-Koo Kang, MD, PhD Principal Investigator Min-Hee Ryu, MD, PhD Sub-Investigator
Location Countries

Korea, Republic of

Verification Date

February 2020

Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Rivoceranib (apatinib) with Paclitaxel

Type: Experimental

Description: 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.

Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

Source: ClinicalTrials.gov