Squamous Cell Carcinoma of the Head and Neck
Conditions
Brief summary
Dalantercept, a soluble form of the activin receptor-like kinase-1 protein, is being studied in patients with squamous cell carcinoma of the head and neck (SCCHN). Dalantercept blocks the development of blood vessels that supply tumors.
Detailed description
For cancer cells to grow, they need to have nutrients supplied to them through blood vessels. The study drug, dalantercept, is designed to work by blocking the growth of those blood vessels and preventing cancer cells from growing. The purpose of this study is to find out if dalantercept can cause SCCHN tumors to shrink or stop growing. This study will also evaluate the safety of dalantercept in patients with SCCHN.
Interventions
BIOLOGICALDalantercept
Subcutaneous dose of dalantercept once every 3 weeks.
Sponsors
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Histologically and/or cytologically confirmed, recurrent or metastatic SCCHN of mucosal origin (oral cavity, oropharynx, hypopharynx or larynx) not amenable to further local therapy (surgery, or radiation including re-irradiation); patients with unknown primary SCCHN presumed to be of head and neck mucosal origin are eligible if they meet all other entry criteria. * Previously treated with at least one platinum-containing regimen or contraindicated for treatment with a platinum containing therapy. (Note: platinum therapy can occur upfront or after recurrence of disease. Failure of platinum therapy is not required.) * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Key
Exclusion criteria
* Nasopharyngeal carcinoma, paranasal sinus, salivary gland or primary skin SCCHN. * Any other active malignancy for which chemotherapy or other anti-cancer therapy is indicated. * Chemotherapy or other anti-cancer therapy or radiation therapy 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. * Treatment with another investigational drug 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. * Major surgery within 4 weeks prior to study day 1 (patients must have recovered completely from any previous surgery prior to study day 1). * Clinically significant cardiovascular risk. * Clinically significant active pulmonary risk. * Clinically significant active bleeding. * Peripheral edema ≥ Grade 1 within 4 weeks prior to study day 1. * Pregnant or lactating female patients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Tumor assessments performed every 6 weeks, up to 30 days after the last dose of dalantercept and/or disease progression, up to approximately 2 years. | ORR is defined as the proportion of patients who met criteria for complete response or partial response. Patients were evaluable for ORR if they had at least one measurable lesion at baseline and at least one disease assessment after baseline. RECIST version 1.1 was used to evaluate efficacy. In addition, patients who developed clinical or radiological progression of disease prior to the scheduled tumor assessment were also considered evaluable for response. The response rate was estimated as the proportion of patients evaluable for response who meet the criteria for complete (CR) and partial response (PR). Per RECIST v1.1 for target lesions and assessed by MRI: complete response (CR), disappearance of all target lesions; partial response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; overall response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | Adverse events captured from first dose of dalantercept through 30 days after last dose of dalantercept. | Number of participants with at least one adverse event as a measure of safety and tolerability. |
| Dalantercept Serum Concentration After Single and Multiple Doses | Up to 43 days from initiation of treatment. | Pharmacokinetic samples were collected pre- and post- dose on Days: 1, 8, 15, 22, 29, and 43. Reported below is AUC0-t (cycle 1). |
| Progression Free Survival (PFS) | Tumor assessments performed every 6 weeks, up to 30 days after the last dose of dalantercept and/or disease progression, up to approximately 2 years. | PFS is defined as the date of the first dose to the first observation of disease progression (according to RECIST v.1.1) or death due to any cause. Progression is defined using RECIST v1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Overall Survival (OS) | Survival captured until death or at a minimum 1 year from first dose of dalantercept. | OS is calculated as the number of months from date of the first dose to the date of death. The last patient treated will be followed for overall survival for 1 year following treatment initiation. |
| Disease Control Rate | Tumor assessments performed every 6 weeks, up to 30 days after the last dose of dalantercept and/or disease progression, up to approximately 2 years. | Disease control rate will be estimated as the proportion of patients evaluable for response who meet the criteria for complete response, partial response, or stable disease. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dalantercept 80 mg Subcutaneous 80 mg dose of dalantercept once every 3 weeks. | 2 |
| Dalantercept 0.6 mg/kg Subcutaneous 0.6 mg/kg dose of dalantercept once every 3 weeks. | 13 |
| Dalantercept 1.2 mg/kg Subcutaneous 1.2 mg/kg dose of dalantercept once every 3 weeks. | 31 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | At the discretion of the sponsor | 0 | 2 | 7 |
| Overall Study | Death | 2 | 11 | 22 |
| Overall Study | Patient unwilling to comply with protoco | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Dalantercept 80 mg | Total | Dalantercept 1.2 mg/kg | Dalantercept 0.6 mg/kg |
|---|---|---|---|---|
| Age, Continuous | 56.5 years STANDARD_DEVIATION 13.4 | 60.5 years STANDARD_DEVIATION 8.5 | 61.1 years STANDARD_DEVIATION 9.5 | 59.6 years STANDARD_DEVIATION 5.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 44 Participants | 31 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 7 Participants | 7 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 34 Participants | 19 Participants | 13 Participants |
| Region of Enrollment United States | 2 participants | 46 participants | 31 participants | 13 participants |
| Sex: Female, Male Female | 2 Participants | 7 Participants | 5 Participants | 0 Participants |
| Sex: Female, Male Male | 0 Participants | 39 Participants | 26 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 13 / 13 | 31 / 31 |
| serious Total, serious adverse events | 1 / 2 | 6 / 13 | 6 / 31 |
Outcome results
Primary
Objective Response Rate (ORR)
ORR is defined as the proportion of patients who met criteria for complete response or partial response. Patients were evaluable for ORR if they had at least one measurable lesion at baseline and at least one disease assessment after baseline. RECIST version 1.1 was used to evaluate efficacy. In addition, patients who developed clinical or radiological progression of disease prior to the scheduled tumor assessment were also considered evaluable for response. The response rate was estimated as the proportion of patients evaluable for response who meet the criteria for complete (CR) and partial response (PR). Per RECIST v1.1 for target lesions and assessed by MRI: complete response (CR), disappearance of all target lesions; partial response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; overall response (OR) = CR + PR.
Time frame: Tumor assessments performed every 6 weeks, up to 30 days after the last dose of dalantercept and/or disease progression, up to approximately 2 years.
Population: The two patients at the 80 mg, fixed-dose level were excluded from the efficacy analysis as the protocol had been amended to incorporate weight-based dosing for the remainder of the study population. 40 received at least one dose of study drug in either the 0.6 mg/kg or 1.2 mg/kg dose groups and had at least one on-treatment tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalantercept 0.6 mg/kg | Objective Response Rate (ORR) | 0 participants |
| Dalantercept 1.2 mg/kg | Objective Response Rate (ORR) | 2 participants |
Secondary
Dalantercept Serum Concentration After Single and Multiple Doses
Pharmacokinetic samples were collected pre- and post- dose on Days: 1, 8, 15, 22, 29, and 43. Reported below is AUC0-t (cycle 1).
Time frame: Up to 43 days from initiation of treatment.
Population: The two patients at the 80 mg, fixed-dose level were excluded from the efficacy analysis as the protocol was amended to incorporate weight-based dosing for the remainder of the study population. 2 patients in the 0.6-mg/kg and 6 in the 1.2-mg/kg cohort had less than 2 measurable serum dalantercept concentrations and were excluded from PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dalantercept 0.6 mg/kg | Dalantercept Serum Concentration After Single and Multiple Doses | 32992 ng*day/mL | Geometric Coefficient of Variation 35.1 |
| Dalantercept 1.2 mg/kg | Dalantercept Serum Concentration After Single and Multiple Doses | 69572 ng*day/mL | Geometric Coefficient of Variation 44.7 |
Secondary
Dalantercept Serum Concentration After Single and Multiple Doses
Pharmacokinetic samples were collected pre- and post- dose on Days: 1, 8, 15, 22, 29, and 43. Reported below is Cmax (cycle 1).
Time frame: Up to 43 days from initiation of treatment.
Population: The two patients at the 80 mg, fixed-dose level were excluded from the efficacy analysis as the protocol was amended to incorporate weight-based dosing for the remainder of the study population. 2 patients in the 0.6-mg/kg and 6 in the 1.2-mg/kg cohort had less than 2 measurable serum dalantercept concentrations and were excluded from PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dalantercept 0.6 mg/kg | Dalantercept Serum Concentration After Single and Multiple Doses | 2446 ng/mL | Geometric Coefficient of Variation 35.1 |
| Dalantercept 1.2 mg/kg | Dalantercept Serum Concentration After Single and Multiple Doses | 5336 ng/mL | Geometric Coefficient of Variation 37.8 |
Secondary
Disease Control Rate
Disease control rate will be estimated as the proportion of patients evaluable for response who meet the criteria for complete response, partial response, or stable disease.
Time frame: Tumor assessments performed every 6 weeks, up to 30 days after the last dose of dalantercept and/or disease progression, up to approximately 2 years.
Population: The two patients at the 80 mg, fixed-dose level were excluded from the efficacy analysis as the protocol had been amended to incorporate weight-based dosing for the remainder of the study population. 40 received at least one dose of study drug in either the 0.6 mg/kg or 1.2 mg/kg dose groups and had at least one on-treatment tumor assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalantercept 0.6 mg/kg | Disease Control Rate | 30.8 percentage of participants |
| Dalantercept 1.2 mg/kg | Disease Control Rate | 44.4 percentage of participants |
Secondary
Overall Survival (OS)
OS is calculated as the number of months from date of the first dose to the date of death. The last patient treated will be followed for overall survival for 1 year following treatment initiation.
Time frame: Survival captured until death or at a minimum 1 year from first dose of dalantercept.
Population: The two patients at the 80 mg, fixed-dose level were excluded from the efficacy analysis as the protocol had been amended to incorporate weight-based dosing for the remainder of the study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dalantercept 0.6 mg/kg | Overall Survival (OS) | 30.9 weeks |
| Dalantercept 1.2 mg/kg | Overall Survival (OS) | 41.3 weeks |
Secondary
Progression Free Survival (PFS)
PFS is defined as the date of the first dose to the first observation of disease progression (according to RECIST v.1.1) or death due to any cause. Progression is defined using RECIST v1.1 as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Tumor assessments performed every 6 weeks, up to 30 days after the last dose of dalantercept and/or disease progression, up to approximately 2 years.
Population: The two patients at the 80 mg, fixed-dose level were excluded from the efficacy analysis as the protocol had been amended to incorporate weight-based dosing for the remainder of the study population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dalantercept 0.6 mg/kg | Progression Free Survival (PFS) | 5.8 weeks |
| Dalantercept 1.2 mg/kg | Progression Free Survival (PFS) | 6.1 weeks |
Secondary
Safety and Tolerability
Number of participants with at least one adverse event as a measure of safety and tolerability.
Time frame: Adverse events captured from first dose of dalantercept through 30 days after last dose of dalantercept.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalantercept 0.6 mg/kg | Safety and Tolerability | 2 participants |
| Dalantercept 1.2 mg/kg | Safety and Tolerability | 13 participants |
| Dalantercept 1.2 mg/kg | Safety and Tolerability | 31 participants |