Apatinib With Pembrolizumab in Previously Treated Advanced Malignancies

NCT03407976 | Terminated Phase 1 DMC FDA Drug

• 1 other identifier: HCI108884
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open label nonrandomized Phase I/ IIA trial designed to assess the safety, tolerability, and efficacy of apatinib in combination with pembrolizumab. Phase I will assess the safety of combining increasing oral daily doses of apatinib with a fixed dose of IV pembrolizumab every three weeks and will determine the RP2D (Recommended Phase 2 Dose). Phase II will assess the efficacy of the RP2D of apatinib in combination with pembrolizumab and provide additional safety and tolerability data in three disease-specific cohorts

Conditions

Advanced Malignancies; Urothelial Carcinoma; MSI-H or dMMR Solid Tumors; Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma

Outcome Measures

Primary Outcomes (2)

• Incidence of dose limiting toxicities (DLTs) of Apatinib in combination with pembrolizumab

  Safety and tolerability of apatinib (rivoceranib) in combination with pembrolizumab in subjects with select advanced malignancies (urothelial carcinoma, MSI-H/dMMR solid tumors including colorectal cancer, and gastric or gastroesophageal junction GEJ adenocarcinoma) and determine the recommended Phase II dose (RP2D) for apatinib in combination with pembrolizumab. Adverse events (AEs), serious adverse events (SAEs), dose-limiting toxicities (DLTs)

  21 days, one cycle

• Objective Response Rate (ORR) (Phase II)

  Objective response rate (ORR) by RECIST 1.1

  12 months

Secondary Outcomes (2)

• Progression Free Survival (PFS)

  5 years (Patients are expected to stay on treatment for approximately 12 months)

• Occurrence of Adverse Events and Serious Adverse Events

  12 months

Study Arms (1)

Apatinib and Pembrolizumab, all patients

EXPERIMENTAL

Drug: Apatinib; Drug: Pembrolizumab

Interventions

Apatinib DRUG

Apatinib oral daily at starting dose 1, Dose Level 2 or Dose Level 3 in phase I, and then whichever is the maximum tolerated dosage will be used for all Phase II patients.

Also known as: YN968D1

Apatinib and Pembrolizumab, all patients

Pembrolizumab DRUG

200 mg Q3 weeks IV

Apatinib and Pembrolizumab, all patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female subject aged ≥ 18 years.
• One of the following advanced solid malignancies which qualifies for standard of care pembrolizumab treatment per FDA approval:
• Locally advanced or metastatic urothelial carcinoma that has progressed during or following platinum-based chemotherapy or within 12 months of neoadjuvant/adjuvant platinum-based therapy. Patients may have received any amount of platinum-based therapy.
• Unresectable or metastatic MSI-H or dMMR solid tumors that have progressed during or following prior treatment and have no satisfactory alternative treatment options (including MSI-H or dMMR colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan).
• Recurrent locally advanced or metastatic, gastric or gastroesophageal junction (GEJ) adenocarcinoma expressing PD-L1 (as determined by an FDA-approved test) that have progressed on or after two or more systemic therapies, including fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate, HER2/neu-targeted therapy.
• Have measurable disease based on RECIST 1.1. (For Phase 2 Subjects Only)
• Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study drug. If the urine test is positive, a serum pregnancy test will be required.
• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for at least 1 year.
• Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study drug.
• ECOG Performance Status ≤ 1.
• Adequate organ function as defined in the protocol
• Recovery to baseline or Grade ≤ 1 CTCAE v4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
• Patients must be able to provide informed consent and be willing to sign an approved consent form that conforms to federal and institutional guidelines

You may not qualify if:

• Previous treatment with and disease progression on a combination of a VEGF inhibitor and an immune checkpoint inhibitor. Patients who have been treated with and have progressed on a single agent VEGF inhibitor OR an immune checkpoint inhibitor will not be excluded.
• Current use of immunosuppressive medication, EXCEPT for the following:
• Topical, ocular, intra-articular, intranasal, and inhaled corticosteroids.
• Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone equivalent.
• Steroids as premedication for hypersensitivity reactions.
• Active autoimmune disease that might deteriorate when receiving an immune-stimulatory agent per treating physician's clinical judgment. Subjects with type 1 diabetes, vitiligo, psoriasis, hypothyroidism, or hyperthyroidism not requiring immunosuppressive medications are eligible.
• Prior organ transplant including allogenic hematopoietic stem cell transplant.
• Active infection requiring intravenous antibiotics (must be completed prior to registration).
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
• Uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
• Cardiovascular disorders:
• Uncontrolled hypertension defined as sustained blood pressure (BP) \> 140 mm Hg systolic or \> 90 mm Hg diastolic despite optimal antihypertensive treatment.
• Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.
• Stroke (including transient ischemic attack \[TIA\]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 6 months before first dose.
• Any history of congenital long QT syndrome.

Sponsors & Collaborators

• University of Utah: lead
• Elevar Therapeutics: collaborator

Study Sites (1)

Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

Related Publications (1)

• Gumbleton M, Allan S, Conway H, Boucher K, Marvin J, Hawks J, Burnett W, Van Brocklin M, Whisenant J, Gilcrease G, Gupta S. A phase I open-label study of the safety and efficacy of apatinib (rivoceranib) administered to patients with advanced malignancies to improve sensitivity to pembrolizumab in the second- or later-line setting (APPEASE). BMC Res Notes. 2023 Feb 16;16(1):16. doi: 10.1186/s13104-023-06283-5.

  PMID: 36797744 DERIVED

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Adenocarcinoma

Interventions

apatinib; pembrolizumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: open label nonrandomized Phase I/ IIA trial designed to assess the safety, tolerability, and efficacy of apatinib in combination with pembrolizumab

Study Record Dates

• First Submitted: January 17, 2018
• First Posted: January 23, 2018
• Study Start: June 19, 2018
• Primary Completion: August 19, 2019
• Study Completion: July 2, 2020
• Last Updated: July 15, 2020

Record last verified: 2020-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)