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

Study Overview
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Brief Summary
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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
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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

Official Title
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A Phase 2 Randomized, Double-Blind Study of Dalantercept and Axitinib Compared to Placebo and Axitinib in Patients With Advanced Renal Cell Carcinoma

Conditions
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Advanced Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Dalantercept and axitinib
* Drug: Placebo and axitinib


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dalantercept 0.9 mg/kg plus axitinib<br>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<br> <br> * Other names: ACE-041, Inlyta;|
| Placebo Comparator: Placebo plus axitinib<br>Subcutaneous injection of normal saline once every 3 weeks and oral axitinib 5 mg BID for continuous dosing | Drug: Placebo and axitinib<br> <br> * Other names: Inlyta;|
| Experimental: Dalantercept 0.6 mg/kg<br>Part 1 dose escalation arm 0.6 mg/kg dalantercept once every 3 weeks | Drug: Dalantercept and axitinib<br> <br> * Other names: ACE-041, Inlyta;|
| Experimental: Dalantercept 0.9 mg/kg<br>Part 1 dose escalation arm 0.9 mg/kg dalantercept once every 3 weeks | Drug: Dalantercept and axitinib<br> <br> * Other names: ACE-041, Inlyta;|
| Experimental: Dalantercept 1.2 mg/kg<br>Part 1 dose escalation arm 1.2 mg/kg dalantercept once every 3 weeks | Drug: Dalantercept and axitinib<br> <br> * Other names: ACE-041, Inlyta;|
| Experimental: Dalantercept 1.5 mg/kg<br>Part 1 dose escalation arm 1.5 mg/kg dalantercept once every 3 weeks | Drug: Dalantercept and axitinib<br> <br> * Other names: ACE-041, Inlyta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: 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. | 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] | Percentage of Part 1 subjects alive at the end of Part 1 of the study. [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) | Objective response rate (ORR) is defined as the number and percentage of patients who have a partial response (PR) or complete response (CR) to therapy. A CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. A PR is defined as a decrease of at least a 30% in the sum of diameters of target lesions, taking as reference the baseline sum diameters. As no subjects in Part 1 experienced a CR, the ORR in Part 1 is defined by the PR | Up to 21.6 months from randomization in Part 1 of the study | 
| Part 1: Disease Control Rate (DCR) | The number and percentage of patients whose disease shrinks or remains stable. DCR is the sum of the complete, partial and stable disease rates. | From randomization up to 21.6 months in Part 1 of the study | 
| Part 1: Duration of Response (DoR) | Response duration is measured from the time measurement criteria are first met for objective response until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded on study. | From randomization up to 21.6 months in Part 1 of the study. | 
| Part 2: Progression Free Survival (PFS) for the Subset of Participants With 2 or More Lines of Prior Systemic Chemotherapy | Progression Free Survival (PFS) for the subset of participants with 2 or more lines of prior systemic chemotherapy. PFS was based upon RECIST 1.1 assessment, as described in outcome measure 2. | 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 | 
| Part 2: Overall Survival. | The number of months from the date of randomization to the date of death. | 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 | 
| Part 2: Objective Response Rate. | Objective response rate (ORR) is defined as the number and percentage of patients who have a partial response (PR) or complete response (CR) to therapy. A CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. A PR is defined as a decrease of at least a 30% in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Assessed at 30 days after last dose of study drug; up to 29.0 months for Part 2 of the study | 
| Part 2: Duration of Response | Response duration is measured from the time measurement criteria are first met for objective response until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded on study. | Assessed at 30 days after the last dose of study drug; up to 29.0 months for Part 2 of the study. | 
| Part 2: Disease Control Rate. | The number and percentage of patients whose disease shrinks or remains stable. DCR is the sum of the complete, partial and stable disease rates. | Assessed at 30 days after last dose of study drug. The time frame for Part 2 was up to 29.0 months |