Study of Dalantercept and Axitinib in Patients With Advanced Renal Cell Carcinoma

NCT01727336 | Terminated Phase 2 Results DMC

• 2 other identifiers: A041-04ACE-041
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 36

Brief Summary

The purpose of Part 1 of this study is to evaluate the safety and tolerability of dalantercept in combination with axitinib in patients with advanced renal cell carcinoma (RCC) to determine the recommended dose level of dalantercept in combination with axitinib for Part 2. The purpose of Part 2 of this study is to determine whether treatment with dalantercept in combination with axitinib prolongs progression free survival (PFS) compared to axitinib alone in patients with advanced renal cell carcinoma (RCC).

Conditions

Advanced Renal Cell Carcinoma

Outcome Measures

Primary Outcomes (2)

• Part 1: Number of Participants With Adverse Events as a Measure of Safety and Tolerability.

  Outcome measure is intended for Part 1 of the study in order to determine recommended dose level for Part 2.

  Assessed from time of first dose to approximately 30 days after last dose. Participants were allowed to remain on treatment until documented disease progression. The time frame for Part 1 of the study was up to 21.6 months

• Part 2: Progression Free Survival (PFS).

  PFS was defined as the time from randomization to the date of first documentation of disease progression based on RECIST (version 1.1) or to death due to any cause, whichever occurred first. Disease progression is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. RECIST 1.1 defines disease progression as an increase of at least a 20% in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression)

  Progression free survival is defined as the time from the date of the randomization to the first documented disease progression (according to RECIST v1.1) or death due to any cause. The Time frame for Part 2 was up to 29.0 months

Secondary Outcomes (10)

• Part 1: Progression Free Survival (PFS).

  The time frame for Part 1 of the study was up to 21.6 months

• Part 1: Overall Survival (OS). [The Time Frame for Part 1 of the Study Was up to 21.6 Months]

  Up to 21.6 months

• Part 1: Objective Response Rate (ORR)

  Up to 21.6 months from randomization in Part 1 of the study

• Part 1: Disease Control Rate (DCR)

  From randomization up to 21.6 months in Part 1 of the study

• Part 1: Duration of Response (DoR)

  From randomization up to 21.6 months in Part 1 of the study.

Other Outcomes (2)

• Part 1: Exploratory PD - Serum BMP9

  From randomization up to 21.6 months in Part 1 of the study

• Part 2: PD Biomarker Activities.

  Assessed at 30 days after the last dose of dalantercept ± 10 days. The time frame for Part 2 was up to 29.0 months.

Study Arms (6)

Dalantercept 0.9 mg/kg plus axitinib

EXPERIMENTAL

Subcutaneous (SC) injection of dalantercept 0.9 mg/kg once every 3 weeks and oral axitinib 5 mg BID for continuous dosing.

Drug: Dalantercept and axitinib

Placebo plus axitinib

PLACEBO COMPARATOR

Subcutaneous injection of normal saline once every 3 weeks and oral axitinib 5 mg BID for continuous dosing

Drug: Placebo and axitinib

Dalantercept 0.6 mg/kg

EXPERIMENTAL

Part 1 dose escalation arm 0.6 mg/kg dalantercept once every 3 weeks

Drug: Dalantercept and axitinib

Dalantercept 0.9 mg/kg

EXPERIMENTAL

Part 1 dose escalation arm 0.9 mg/kg dalantercept once every 3 weeks

Drug: Dalantercept and axitinib

Dalantercept 1.2 mg/kg

EXPERIMENTAL

Part 1 dose escalation arm 1.2 mg/kg dalantercept once every 3 weeks

Drug: Dalantercept and axitinib

Dalantercept 1.5 mg/kg

EXPERIMENTAL

Part 1 dose escalation arm 1.5 mg/kg dalantercept once every 3 weeks

Drug: Dalantercept and axitinib

Interventions

Dalantercept and axitinib DRUG

Also known as: ACE-041, Inlyta

Dalantercept 0.6 mg/kg; Dalantercept 0.9 mg/kg; Dalantercept 0.9 mg/kg plus axitinib; Dalantercept 1.2 mg/kg; Dalantercept 1.5 mg/kg

Placebo and axitinib DRUG

Also known as: Inlyta

Placebo plus axitinib

Eligibility Criteria

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

You may qualify if:

• Histologically confirmed, advanced, predominantly clear cell renal cell carcinoma (RCC).
• Part 1: Progression of disease following up to three lines of prior therapy, including at least one approved VEGF receptor tyrosine kinase inhibitor for RCC. Adjuvant therapy is permitted as one line of prior therapy.
• Part 2: Progression of disease following one VEGF pathway inhibitor for RCC (e.g. sunitinib, pazopanib, sorafenib, bevacizumab, tivozanib, or cabozantinib) inclusive of adjuvant therapy if there was documented disease progression during treatment. Patients may have received one additional line of an approved mTOR kinase inhibitor (e.g. everolimus, temsirolimus). Prior exposure to investigational and/or approved anticancer immune therapies is permitted.
• A minimum of 1 week since the last dose of prior therapy (a minimum of 4 weeks since anticancer immune therapy or bevacizumab +/- interferon).
• Measurable disease that is evaluable by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Life expectancy of at least 12 weeks.
• Clinical laboratory values within acceptable ranges within 72 hours prior to study day 1.

You may not qualify if:

• Clinically significant organ/system disease unrelated to RCC that in the judgment of the investigator should preclude treatment with dalantercept or axitinib.
• Clinically significant cardiovascular risk.
• Known CNS metastases or leptomeningeal disease:
• For Part 1, patients with CNS metastases treated with whole brain radiotherapy, gamma knife, and/or surgery who are considered stable by CNS imaging and are not being treated with corticosteroids 6 weeks prior to study day 1 may be enrolled.
• For Part 2, patients with CNS metastases treated stereotactic radio-surgery (SRS), and/or surgery who are considered stable by CNS imaging for at least 2 months prior to enrollment and are not being treated with corticosteroids 6 weeks prior to study day 1 may be enrolled.
• Any active malignancy, other than RCC, for which chemotherapy or other anti-cancer therapy is indicated. Patients with adequately treated non-melanoma skin cancer, in situ cancer, or other cancer from which the subject has been disease-free for at least 3 years will be permitted.
• Any lesion invading or having encasement ≥ 180 degrees around the wall of a major blood vessel as assessed by computed tomography (CT) scan and/or magnetic resonance imaging (MRI).
• Radiotherapy within 2 weeks prior to study day 1.
• Lack of recovery from toxic effects of previous treatment for RCC ≤ grade 1 with the exception of alopecia, unless stabilized under adequate medical control.
• Patients undergoing renal dialysis.
• Major surgery within 4 weeks prior to study day 1 (patients must have recovered completely from any previous surgery prior to study day 1).
• Any active infection requiring antibiotic therapy within 2 weeks of study day 1.
• Anti-coagulation therapy. Aspirin, other anti-platelet agents, and low molecular weight heparin are permitted unless the investigator deems the patient is at a significant risk for bleeding.
• Current use or anticipated inability to avoid potent CYP3A4/5 inhibitors or inducers (please refer to the Inlyta® \[axitinib\] prescribing information) during participation in the study.
• Peripheral edema requiring medical intervention within 2 weeks prior to study day 1.

Sponsors & Collaborators

• Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA: lead

Study Sites (36)

Arizona Oncology Associates, PC - HOPE

Tucson, Arizona, 85718, United States

Location

Highlands Oncology Group, PA

Fayetteville, Arkansas, 72758, United States

Location

University of California Irvine Medical Center

Irvine, California, 92697, United States

Location

University of California, Los Angeles (UCLA) - Institute of Urologic Oncology

Los Angeles, California, 90095, United States

Location

Stanford Hospital and Clinics

Stanford, California, United States

Location

Rocky Mountain Cancer Centers

Aurora, Colorado, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, United States

Location

University of Miami

Miami, Florida, United States

Location

H. Lee Moffitt Cancer Center & Research Institute

Tampa, Florida, United States

Location

Loyola University Chicago

Chicago, Illinois, United States

Location

Indiana University Health Melvin & Bren Simon Cancer Center

Indianapolis, Indiana, United States

Location

Beth Israel Deaconess Med Center

Boston, Massachusetts, United States

Location

Lahey Hospital & Medical Center

Burlington, Massachusetts, United States

Location

Nebraska Methodist Hospital

Omaha, Nebraska, United States

Location

Comprehensive Cancer Centers of Nevada

Las Vegas, Nevada, United States

Location

Cancer Center Hackensack UMC

Hackensack, New Jersey, United States

Location

University of New Mexico

Albuquerque, New Mexico, United States

Location

New York Oncology Hematology, P.C.

Albany, New York, United States

Location

North Shore LIJ Center for Advance Medicine

Lake Success, New York, United States

Location

Mem Sloan Kettering Cancer Center

New York, New York, United States

Location

NYU Cancer Institute

New York, New York, United States

Location

Levin Cancer Institute

Charlotte, North Carolina, United States

Location

Cleveland Clinic

Cleveland, Ohio, United States

Location

Northwest Cancer Specialists, P.C.

Tualatin, Oregon, United States

Location

Saint Luke's University Health Network

Bethlehem, Pennsylvania, United States

Location

Penn State Milton S- Hershey Medical Center

Hershey, Pennsylvania, United States

Location

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Location

University of Pittsburgh, Hillman Cancer Center

Pittsburgh, Pennsylvania, United States

Location

Medical University of South Carolina

Charleston, South Carolina, United States

Location

Texas Oncology-South Austin

Austin, Texas, United States

Location

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, United States

Location

Texas Oncology-El Paso Cancer Treatment Center Grandview

El Paso, Texas, United States

Location

Texas Oncology - Memorial City

Houston, Texas, United States

Location

Texas Oncology - Tyler and Longview

Tyler, Texas, United States

Location

Shenandoah Oncology P.C.

Winchester, Virginia, United States

Location

University of Wisconsin, Carbone Cancer Center

Madison, Wisconsin, United States

Location

Related Publications (1)

• Voss MH, Bhatt RS, Vogelzang NJ, Fishman M, Alter RS, Rini BI, Beck JT, Joshi M, Hauke R, Atkins MB, Burgess E, Logan TF, Shaffer D, Parikh R, Moazzam N, Zhang X, Glasser C, Sherman ML, Plimack ER. A phase 2, randomized trial evaluating the combination of dalantercept plus axitinib in patients with advanced clear cell renal cell carcinoma. Cancer. 2019 Jul 15;125(14):2400-2408. doi: 10.1002/cncr.32061. Epub 2019 Apr 5.

  PMID: 30951193 DERIVED

MeSH Terms

Interventions

ALK1-Fc fusion protein, human; Axitinib

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Indazoles; Pyrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Limitations and Caveats

All 131 patients in Part 2 discontinued from the study; the most frequent reasons were (i) study terminated at the discretion of the sponsor \[86 patients (65.6%)\] and (ii) death \[36 patients (27.5%)\]. The discontinuations prior to planned sample collections, as outlined in the protocol schedule of events, precluded the ability to carry out all planned analyses, including but not limited to PK analyses. Dalantercept PK in patients with advanced cancer has been reported previously.

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Part 1 of the study involved a dose escalation phase to select a dose for Part 2 of the study. In Part 1, a total of 29 subjects escalated through 3 dose levels of dalantercept: 0.6, 0.9 and 1.2 mg/kg once every 3 weeks. In Part 2, dalantercept (0.9 mg/kg once every 3 weeks) plus axitinib 5 mg PO BID) was compared with placebo plus axitinib 5 mg PO BID. Part 2 enrolled 131 subjects for a total of 160 subjects in the study

Study Record Dates

• First Submitted: November 8, 2012
• First Posted: November 16, 2012
• Study Start: December 1, 2012
• Primary Completion: June 1, 2017
• Study Completion: November 1, 2017
• Last Updated: October 6, 2022
• Results First Posted: May 24, 2021

Record last verified: 2021-09

Locations

US (36)