Advanced Renal Cell Carcinoma
Conditions
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
Interventions
DRUGDalantercept and axitinib
DRUGPlacebo and axitinib
Sponsors
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
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
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 2: Progression Free Survival (PFS). | 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 | 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) |
| Part 1: Number of Participants With Adverse Events as a Measure of Safety and Tolerability. | 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 | Outcome measure is intended for Part 1 of the study in order to determine recommended dose level for Part 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Percentage of Part 1 subjects alive at the end of Part 1 of the study. \[The time frame for Part 1 of the study was up to 21.6 months\] |
| Part 1: Objective Response Rate (ORR) | Up to 21.6 months from randomization in Part 1 of the study | 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 |
| Part 1: Disease Control Rate (DCR) | From randomization up to 21.6 months in Part 1 of the study | The number and percentage of patients whose disease shrinks or remains stable. DCR is the sum of the complete, partial and stable disease rates. |
| Part 1: Duration of Response (DoR) | From randomization up to 21.6 months in Part 1 of the study. | 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. |
| Part 2: Overall Survival. | 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 | The number of months from the date of randomization to the date of death. |
| Part 2: Objective Response Rate. | Assessed at 30 days after last dose of study drug; up to 29.0 months for Part 2 of the study | 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. |
| Part 2: Duration of Response | Assessed at 30 days after the last dose of study drug; up to 29.0 months for Part 2 of the study. | 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. |
| Part 2: Disease Control Rate. | Assessed at 30 days after last dose of study drug. The time frame for Part 2 was up to 29.0 months | The number and percentage of patients whose disease shrinks or remains stable. DCR is the sum of the complete, partial and stable disease rates. |
| Part 2: Progression Free Survival (PFS) for the Subset of Participants With 2 or More Lines of Prior Systemic Chemotherapy | 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 | 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. |
| Part 1: Progression Free Survival (PFS). | The time frame for Part 1 of the study was up to 21.6 months | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Exploratory PD - Serum BMP9 | From randomization up to 21.6 months in Part 1 of the study | Exploratory analysis. Absolute change from baseline in serum Bone Morphogenetic Protein 9 (BMP9) |
| 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. | Exploratory analysis. Absolute change from baseline in serum Bone Morphogenetic Protein 9 (BMP9) |
Countries
United States
Participant flow
Pre-assignment details
In the Part 1 dose escalation portion of the study, 4 dose levels of dalantercept plus an expansion cohort were planned. However, dose escalation was suspended following the 1.2 mg/kg dose level and additional subjects were added to the 1.2 mg/kg dose cohort, which represented the expansion; no subjects were enrolled in the 1.5 mg/kg dose level.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 Dalantercept 0.6 mg/kg Dose escalation cohort 1: dalantercept 0.6 mg/kg | 6 |
| Part 1 Dalantercept 0.9 mg/kg Dose escalation cohort 2: dalantercept 0.9 mg/kg | 9 |
| Part 1 Dalantercept 1.2 mg/kg Dose escalation cohort 3: dalantercept 1.2 mg/kg | 14 |
| Part 1 Dalantercept 1.5 mg/kg Dose escalation cohort 4: dalantercept 1.5 mg/kg | 0 |
| Part 2 Dalantercept 0.9 mg/kg Plus Axitinib Subcutaneous (SC) injection of Dalantercept once every 3 weeks and oral axitinib 5 mg BID for continuous dosing. | 63 |
| Placebo Plus Axitinib Subcutaneous injection of normal saline once every 3 weeks and oral axitinib 5 mg BID for continuous dosing | 68 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Part 1 Dalantercept Dose Escalation | Adverse Event | 0 | 1 | 5 | 0 | 0 | 0 |
| Part 1 Dalantercept Dose Escalation | Lack of Efficacy | 3 | 1 | 3 | 0 | 0 | 0 |
| Part 2 Blinded | Death | 0 | 0 | 0 | 0 | 20 | 16 |
| Part 2 Blinded | Lack of Efficacy | 0 | 0 | 0 | 0 | 42 | 44 |
| Part 2 Blinded | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 1 |
| Part 2 Blinded | use of prohibited medications | 0 | 0 | 0 | 0 | 1 | 3 |
| Part 2 Blinded | Withdrawal by Subject | 0 | 0 | 0 | 0 | 0 | 4 |
Baseline characteristics
| Characteristic | Part 1 Dalantercept 0.6 mg/kg | Part 1 Dalantercept 0.9 mg/kg | Part 1 Dalantercept 1.2 mg/kg | Part 2 Dalantercept 0.9 mg/kg Plus Axitinib | Placebo Plus Axitinib | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 64.3 years STANDARD_DEVIATION 7.2 | 56.2 years STANDARD_DEVIATION 9.2 | 61.5 years STANDARD_DEVIATION 10.9 | 62.8 years STANDARD_DEVIATION 8.1 | 58.9 years STANDARD_DEVIATION 10.1 | 60.7 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 6 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 8 Participants | 13 Participants | 58 Participants | 58 Participants | 143 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment United States | 6 participants | 9 participants | 14 participants | 63 participants | 68 participants | 160 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants | 22 Participants | 28 Participants | 56 Participants |
| Sex: Female, Male Male | 5 Participants | 7 Participants | 11 Participants | 41 Participants | 40 Participants | 104 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 2 / 9 | 5 / 14 | 0 / 0 | 20 / 63 | 16 / 68 |
| other Total, other adverse events | 6 / 6 | 9 / 9 | 14 / 14 | 0 / 0 | 61 / 62 | 64 / 64 |
| serious Total, serious adverse events | 2 / 6 | 1 / 9 | 6 / 14 | 0 / 0 | 19 / 62 | 16 / 64 |
Outcome results
Primary
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.
Time frame: 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
Population: Safety Analysis Set (SAF) consisted of all patients who received at least 1 dose of study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 1: Number of Participants With Adverse Events as a Measure of Safety and Tolerability. | 6 Participants |
| Part 1 Dalantercept 0.9 mg/kg | Part 1: Number of Participants With Adverse Events as a Measure of Safety and Tolerability. | 9 Participants |
| Part 1 Dalantercept 1.2 mg/kg | Part 1: Number of Participants With Adverse Events as a Measure of Safety and Tolerability. | 14 Participants |
Primary
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)
Time frame: 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
Population: The All Treated Set (ATS) included all randomized patients who received any study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 2: Progression Free Survival (PFS). | 6.8 Months |
| Part 1 Dalantercept 0.9 mg/kg | Part 2: Progression Free Survival (PFS). | 5.6 Months |
Secondary
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.
Time frame: From randomization up to 21.6 months in Part 1 of the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 1: Disease Control Rate (DCR) | 3 Participants |
| Part 1 Dalantercept 0.9 mg/kg | Part 1: Disease Control Rate (DCR) | 5 Participants |
| Part 1 Dalantercept 1.2 mg/kg | Part 1: Disease Control Rate (DCR) | 6 Participants |
Secondary
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.
Time frame: From randomization up to 21.6 months in Part 1 of the study.
Population: Full Analysis Set; all subjects randomized in Part 1 of the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 1: Duration of Response (DoR) | 3 months |
| Part 1 Dalantercept 0.9 mg/kg | Part 1: Duration of Response (DoR) | 6.9 months |
| Part 1 Dalantercept 1.2 mg/kg | Part 1: Duration of Response (DoR) | 10 months |
Secondary
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
Time frame: Up to 21.6 months from randomization in Part 1 of the study
Population: Full Analysis Set; all subjects randomized in Part 1 of the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 1: Objective Response Rate (ORR) | 2 Participants |
| Part 1 Dalantercept 0.9 mg/kg | Part 1: Objective Response Rate (ORR) | 3 Participants |
| Part 1 Dalantercept 1.2 mg/kg | Part 1: Objective Response Rate (ORR) | 2 Participants |
Secondary
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. \[The time frame for Part 1 of the study was up to 21.6 months\]
Time frame: Up to 21.6 months
Population: Full Analysis Set; all subjects randomized in Part 1 of the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 1: Overall Survival (OS). [The Time Frame for Part 1 of the Study Was up to 21.6 Months] | 4 Participants |
| Part 1 Dalantercept 0.9 mg/kg | Part 1: Overall Survival (OS). [The Time Frame for Part 1 of the Study Was up to 21.6 Months] | 7 Participants |
| Part 1 Dalantercept 1.2 mg/kg | Part 1: Overall Survival (OS). [The Time Frame for Part 1 of the Study Was up to 21.6 Months] | 9 Participants |
Secondary
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.
Time frame: The time frame for Part 1 of the study was up to 21.6 months
Population: Full Analysis Set; all subjects randomized in Part 1 of the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 1: Progression Free Survival (PFS). | 5.5 Months |
| Part 1 Dalantercept 0.9 mg/kg | Part 1: Progression Free Survival (PFS). | 21.6 Months |
| Part 1 Dalantercept 1.2 mg/kg | Part 1: Progression Free Survival (PFS). | 6.9 Months |
Secondary
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.
Time frame: Assessed at 30 days after last dose of study drug. The time frame for Part 2 was up to 29.0 months
Population: The All Treated Set (ATS) included all randomized patients who received any study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 2: Disease Control Rate. | 48 Participants |
| Part 1 Dalantercept 0.9 mg/kg | Part 2: Disease Control Rate. | 50 Participants |
Secondary
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.
Time frame: Assessed at 30 days after the last dose of study drug; up to 29.0 months for Part 2 of the study.
Population: The All Treatment Set (ATS) included all randomized patients who received any study drug. Please see Outcome Measure 5 for Objective Response Rate data. Since there were too few participants with events, an estimation of response duration was not able to be calculated due to the early termination of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 2: Duration of Response | NA Months |
| Part 1 Dalantercept 0.9 mg/kg | Part 2: Duration of Response | NA Months |
Secondary
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.
Time frame: Assessed at 30 days after last dose of study drug; up to 29.0 months for Part 2 of the study
Population: The All Treated Set (ATS) included all randomized patients who received any study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 2: Objective Response Rate. | 11 Participants |
| Part 1 Dalantercept 0.9 mg/kg | Part 2: Objective Response Rate. | 15 Participants |
Secondary
Part 2: Overall Survival.
The number of months from the date of randomization to the date of death.
Time frame: 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
Population: The All Treated Set (ATS) included all randomized patients who received any study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 2: Overall Survival. | 13.0 Months |
| Part 1 Dalantercept 0.9 mg/kg | Part 2: Overall Survival. | 14.7 Months |
Secondary
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.
Time frame: 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
Population: Subgroup of Part 2 participants:~24 of 63 participants in the dalantercept arm and 22 of 68 participants in the placebo arm had at least 2 lines of prior systemic chemotherapy
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 2: Progression Free Survival (PFS) for the Subset of Participants With 2 or More Lines of Prior Systemic Chemotherapy | 8.1 Months |
| Part 1 Dalantercept 0.9 mg/kg | Part 2: Progression Free Survival (PFS) for the Subset of Participants With 2 or More Lines of Prior Systemic Chemotherapy | 7.0 Months |
Other Pre-specified
Part 1: Exploratory PD - Serum BMP9
Exploratory analysis. Absolute change from baseline in serum Bone Morphogenetic Protein 9 (BMP9)
Time frame: From randomization up to 21.6 months in Part 1 of the study
Population: All subjects randomized to Part 1 of the study and treated with at least 1 dose of dalantercept. Given the high degree of variability in serum BMP9 levels in study subjects \[Baseline value 23.55 ng/mL (SD 20.54 ng/mL)\] and the relative small numbers of subjects in each treatment arm, it was decided that the best way to understand a treatment effect was to conduct a pooled analysis of all 29 Part 1 subjects for the comparison of change from Baseline.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 1: Exploratory PD - Serum BMP9 | -11.5 ng/mL | Standard Deviation 2.58 |
Other Pre-specified
Part 2: PD Biomarker Activities.
Exploratory analysis. Absolute change from baseline in serum Bone Morphogenetic Protein 9 (BMP9)
Time frame: Assessed at 30 days after the last dose of dalantercept ± 10 days. The time frame for Part 2 was up to 29.0 months.
Population: The All Treated Set (ATS) included all randomized patients who received any study drug, and for whom sufficient blood sample was available to assess the exploratory biomarker.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1 Dalantercept 0.6 mg/kg | Part 2: PD Biomarker Activities. | -53.34 pg/mL | Standard Deviation 37.87 |
| Part 1 Dalantercept 0.9 mg/kg | Part 2: PD Biomarker Activities. | 8.55 pg/mL | Standard Deviation 86.32 |