Clinical trial NCT01727336: Study of Dalantercept and Axitinib in Patients With Advanced Renal Cell Carcinoma
Official title: A Phase 2 Randomized, Double-Blind Study of Dalantercept and Axitinib Compared to Placebo and Axitinib in Patients With Advanced Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Advanced Renal Cell Carcinoma
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2012-11-16
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: 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
Primary purpose: TREATMENT

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).

Detailed description: In Part 1 of the study, groups of subjects received escalating doses of dalantercept; 0.6, 0.9 and 1.2 mg/kg in sequential groups. All subjects received concurrent axitinib 5 mg PO BID. A total of 29 subjects were enrolled i Part 1 of the study.

In Part 2, dalantercept at 0.9 mg/kg once every 3 weeks plus axitinib 5 mg PO BID was compared to placebo plus axitinib 5 mg PO BID. A total of 131 subjects were enrolled in Part 2 for a total of 160 in the study

Eligibility criteria: Key Inclusion Criteria:

* 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.

Key Exclusion Criteria:

* 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.
* Bleeding diathesis including clinically significant platelet disorders or active hemoptysis (defined as bright red blood of ≥ 1/2 teaspoon \[2.5 mL\] in any 24 hour period) within 6 months prior to study day 1. For clinically significant epistaxis within 4 weeks prior to study day 1, no risk of further bleeding must be clearly documented.
* Known history of hereditary hemorrhagic telangiectasia (HHT).
* Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infections or positive human immunodeficiency virus (HIV) antibody results. Patients with sustained virologic response to HCV treatment or immunity to HBV from prior infection without cirrhosis may be included.
* History of severe (defined as ≥ grade 3, using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0 \[NCI-CTCAE\] v4 current active minor version) allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients (10 mM Tris buffered saline) in the investigational agent.
* Any prior treatment with dalantercept or any other agent targeting ALK1 pathway.
* Any prior treatment with axitinib.
* A morbidity (per the prescribing information) that would require starting a patient at a reduced dose of axitinib.
* Treatment with another investigational drug (with the exception of anticancer immune therapy) or device, or approved therapy for investigational use, within 5 times the half-life of the drug or within 3 weeks prior to study day 1 if the half life is not known.
* Pregnant or lactating female patients.

Primary outcomes:
measure: Part 1: Number of Participants With Adverse Events as a Measure of Safety and Tolerability.
timeFrame: 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
measure: Part 2: Progression Free Survival (PFS).
timeFrame: 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:
measure: Part 1: Progression Free Survival (PFS).
timeFrame: The time frame for Part 1 of the study was up to 21.6 months
measure: Part 1: Overall Survival (OS). [The Time Frame for Part 1 of the Study Was up to 21.6 Months]
timeFrame: Up to 21.6 months
measure: Part 1: Objective Response Rate (ORR)
timeFrame: Up to 21.6 months from randomization in Part 1 of the study
measure: Part 1: Disease Control Rate (DCR)
timeFrame: From randomization up to 21.6 months in Part 1 of the study
measure: Part 1: Duration of Response (DoR)
timeFrame: From randomization up to 21.6 months in Part 1 of the study.
measure: Part 2: Progression Free Survival (PFS) for the Subset of Participants With 2 or More Lines of Prior Systemic Chemotherapy
timeFrame: 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
measure: Part 2: Overall Survival.
timeFrame: Patients to be contacted every 3 months for up to 12 months (anticipated) for survival follow-up, as well as tumor assessment scans if progression of disease has not previously been documented. The time frame for Part 2 was up to 29.0 months
measure: Part 2: Objective Response Rate.
timeFrame: Assessed at 30 days after last dose of study drug; up to 29.0 months for Part 2 of the study
measure: Part 2: Duration of Response
timeFrame: Assessed at 30 days after the last dose of study drug; up to 29.0 months for Part 2 of the study.
measure: Part 2: Disease Control Rate.
timeFrame: Assessed at 30 days after last dose of study drug. The time frame for Part 2 was up to 29.0 months
Other outcomes:
measure: Part 1: Exploratory PD - Serum BMP9
timeFrame: From randomization up to 21.6 months in Part 1 of the study
measure: Part 2: PD Biomarker Activities.
timeFrame: Assessed at 30 days after the last dose of dalantercept ± 10 days. The time frame for Part 2 was up to 29.0 months.
Locations:
city: Tucson
country: United States
facility: Arizona Oncology Associates, PC - HOPE
state: Arizona
city: Fayetteville
country: United States
facility: Highlands Oncology Group, PA
state: Arkansas
city: Irvine
country: United States
facility: University of California Irvine Medical Center
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles (UCLA) - Institute of Urologic Oncology
state: California
city: Stanford
country: United States
facility: Stanford Hospital and Clinics
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers
state: Colorado
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute
state: Florida
city: Chicago
country: United States
facility: Loyola University Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Health Melvin & Bren Simon Cancer Center
state: Indiana
city: Boston
country: United States
facility: Beth Israel Deaconess Med Center
state: Massachusetts
city: Burlington
country: United States
facility: Lahey Hospital & Medical Center
state: Massachusetts
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Las Vegas
country: United States
facility: Comprehensive Cancer Centers of Nevada
state: Nevada
city: Hackensack
country: United States
facility: Cancer Center Hackensack UMC
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Albany
country: United States
facility: New York Oncology Hematology, P.C.
state: New York
city: Lake Success
country: United States
facility: North Shore LIJ Center for Advance Medicine
state: New York
city: New York
country: United States
facility: Mem Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: NYU Cancer Institute
state: New York
city: Charlotte
country: United States
facility: Levin Cancer Institute
state: North Carolina
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Tualatin
country: United States
facility: Northwest Cancer Specialists, P.C.
state: Oregon
city: Bethlehem
country: United States
facility: Saint Luke's University Health Network
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State Milton S- Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh, Hillman Cancer Center
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Austin
country: United States
facility: Texas Oncology-South Austin
state: Texas
city: Dallas
country: United States
facility: Texas Oncology - Baylor Charles A. Sammons Cancer Center
state: Texas
city: El Paso
country: United States
facility: Texas Oncology-El Paso Cancer Treatment Center Grandview
state: Texas
city: Houston
country: United States
facility: Texas Oncology - Memorial City
state: Texas
city: Tyler
country: United States
facility: Texas Oncology - Tyler and Longview
state: Texas
city: Winchester
country: United States
facility: Shenandoah Oncology P.C.
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin, Carbone Cancer Center
state: Wisconsin
Study officials:
References:
citation: 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.