Squamous Cell Carcinoma of the Anal Canal
Conditions
Keywords
Squamous cell carcinoma, carboplatin, paclitaxel, PD-1 Inhibitor, Anal Cancer, SCAC
Brief summary
This study is a Phase 3 global, multicenter, placebo-controlled double-blind randomized study that will enroll participants with inoperable locally recurrent or metastatic SCAC not previously treated with systemic chemotherapy.
Interventions
DRUGcarboplatin
carboplatin will be administered intravenous on Day 1 of each 28 day cycle
DRUGpaclitaxel
paclitaxel will be administered intravenous on Days 1,8, and 15 of each 28 day cycle
DRUGretifanlimab
retifanlimab will be administered intravenous on Day 1 of each 28 day cycle
Sponsors
Incyte Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double Blind
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Able to comprehend and willing to sign a written ICF for the study. * Are 18 years of age or older (or as applicable per local country requirements). * Histologically or cytologically verified, inoperable locally recurrent or metastatic SCAC. * No prior systemic therapy other than the following: a. Chemotherapy administered concomitantly with radiotherapy as a radiosensitizing agent is permitted. b. Prior neoadjuvant or adjuvant therapy if completed ≥ 6 months before study entry. * Has measurable disease per RECIST v1.1 as determined by local site investigator/radiology assessment. Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually not considered measurable unless there has been demonstrated progression in the lesion. * Able and willing to provide adequate tissue sample and whole blood sample with central testing result prior to randomization. Biopsy for archival samples should have occurred within 9 months prior to randomization. * ECOG performance status 0 to 1. * If HIV-positive, then must be stable as defined by: a. CD4+ count ≥ 200/μL, b. Undetectable viral load per standard of care assay, c. Receiving antiretroviral therapy (ART/HAART) for at least 4 weeks prior to study enrollment, and have not experienced any HIV-related opportunistic infection for at least 4 weeks prior to study enrollment. * Willingness to avoid pregnancy or fathering children
Exclusion criteria
* Has received prior PD-(L)1 directed therapy * Has received prior radiotherapy with or without radiosensitizing chemotherapy within 28 days of Cycle 1 Day 1 except for palliative radiation (30 Gy or less) which is restricted for 14 days of Cycle 1 Day 1 (note: all toxicities associated should have resolved to Grade ≤ 1). * Participants with laboratory outside of the protocol defined ranges. * History of second malignancy within 3 years (with exceptions). * Clinically significant pulmonary, cardiac, gastrointestinal or autoimmune disorders. * Active bacterial, fungal, or viral infections, including hepatitis A, B, and C and IV antibiotic use within 7 days of Cycle 1 Day 1. * Receipt of a live vaccine within 28 days of planned start of study therapy. * History of organ transplant, including allogeneic stem cell transplantation. * Known active CNS metastases and/or carcinomatous meningitis. * Known hypersensitivity to platinum, paclitaxel, another monoclonal antibody, or any of the excipients that cannot be controlled with standard measures (eg, antihistamines, corticosteroids). * Participant is pregnant or breastfeeding. * Current use of protocol defined prohibited medication. * Has pre-existing peripheral neuropathy that is ≥ Grade 2 by CTCAE v5. * Inability or unlikely, in the opinion of the investigator, to comply with the Protocol requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | up to 33.9 months | PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD), according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review committee (BICR), or death due to any cause, whichever occurred first. PD: progression of a target or non-target lesion or presence of a new lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | up to 445 days | ORR was defined as the percentage of participants with a confirmed CR or PR at any post-Baseline visit before the first PD or new anticancer therapy, according to RECIST v1.1 as determined by BICR. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. |
| Duration of Response (DOR) | up to 32.1 months | DOR was defined as the time from the first documented confirmed response (CR or PR) determined by BICR to the time of first documented disease progression per RECIST v1.1 or death due to any cause. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. |
| Disease Control Rate (DCR) | up to 445 days | DCR was defined as the percentage of participants maintaining either a confirmed overall response of CR or PR or stable disease (SD) at any post-Baseline visit before the first PD or new anticancer therapy, according to RECIST v1.1 as determined by BICR. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD. |
| Number of Participants With Any Treatment-emergent Adverse Event (TEAE ) During the Randomized Period | up to 535 days | An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as any AEs either reported for the first time or the worsening of a pre-existing events after the first dose of study treatment and within 90 days of the last administration of retifanlimab/placebo, or within 30 days of the last chemotherapy. AEs that occurred after new anticancer therapy were be excluded. |
| Number of Participants With Any TEAE Leading to Discontinuation of Study Drug During the Randomized Period | up to 535 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as any AEs either reported for the first time or the worsening of a pre-existing events after the first dose of study treatment and within 90 days of the last administration of retifanlimab/placebo, or within 30 days of the last chemotherapy. AEs that occurred after new anticancer therapy were be excluded. |
| Number of Participants With Any TEAE During the Open-label Monotherapy Period | up 463 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as any AEs either reported for the first time or the worsening of a pre-existing events after the first dose of study treatment and within 90 days of the last administration of retifanlimab/placebo. AEs that occurred after new anticancer therapy were be excluded. |
| Number of Participants With Any TEAE Leading to Discontinuation of Study Drug During the Open-label Monotherapy Period | up 463 days | An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as any AEs either reported for the first time or the worsening of a pre-existing events after the first dose of study treatment and within 90 days of the last administration of retifanlimab/placebo. AEs that occurred after new anticancer therapy were be excluded. |
| Cmax of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel | preinfusion on Day 1 of Cycles 1, 2, 4, 6, 8, and 12; immediately after infusion on Day 1 of Cycles 1 and 4 | Cmax was defined as the maximum observed plasma concentration of retifanlimab. |
| Cmin of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel | preinfusion on Day 1 of Cycles 1, 2, 4, 6, 8, and 12; immediately after infusion on Day 1 of Cycles 1 and 4 | Cmin was defined as the minimum observed plasma concentration of retifanlimab. |
| Tmax of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel | preinfusion on Day 1 of Cycles 1, 2, 4, 6, 8, and 12; immediately after infusion on Day 1 of Cycles 1 and 4 | tmax was defined as the time to the maximum serum concentration of retifanlimab. |
| Overall Survival | up to 56.5 months | Overall survival was defined as the time from the date of randomization until the date of death due to any cause. |
| AUC of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel | preinfusion on Day 1 of Cycles 1, 2, 4, 6, 8, and 12; immediately after infusion on Day 1 of Cycles 1 and 4 | AUC was defined as the area under the serum concentration versus time curve. |
Countries
Australia, Belgium, Denmark, France, Germany, Italy, Japan, Norway, Puerto Rico, Spain, Sweden, United Kingdom, United States
Participant flow
Pre-assignment details
This study randomized participants at 70 study centers in Australia, Belgium, Germany, Denmark, Spain, France, the United Kingdom, Italy, Japan, Norway, Puerto Rico, Sweden, and the United States.
Participants by arm
| Arm | Count |
|---|---|
| Retifanlimab 500 mg Q4W + Chemotherapy Participants received retifanlimab 500 milligrams (mg) every 4 weeks (Q4W) for up to thirteen 28-day cycles (1 year) in the absence of disease progression, intolerable toxicity, death, withdrawal of consent, being lost to follow-up, or premature discontinuation of all assigned study drug administration or for any other reason. Participants also received the standard-of-care chemotherapy regimen of up to 6 induction cycles (24 weeks) of carboplatin (AUC5 on Day 1) and paclitaxel (80 mg per meters squared \[mg/m\^2\] on Days 1, 8, and 15). | 154 |
| Placebo + Chemotherapy Participants received matching placebo Q4W for up to thirteen 28-day cycles (1 year) in the absence of disease progression, intolerable toxicity, death, withdrawal of consent, being lost to follow-up, or premature discontinuation of all assigned study drug administration or for any other reason. | 154 |
| Total | 308 |
Baseline characteristics
| Characteristic | Retifanlimab 500 mg Q4W + Chemotherapy | Total | Placebo + Chemotherapy |
|---|---|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 9.81 | 61.3 years STANDARD_DEVIATION 10.15 | 61.1 years STANDARD_DEVIATION 10.51 |
| Race/Ethnicity, Customized Asian | 10 Participants | 18 Participants | 8 Participants |
| Race/Ethnicity, Customized Black/African-American | 3 Participants | 5 Participants | 2 Participants |
| Race/Ethnicity, Customized Captured as "Other" in Database | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 13 Participants | 21 Participants | 8 Participants |
| Race/Ethnicity, Customized Mexican | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Mixed: White/Indian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Multiple Races | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 129 Participants | 261 Participants | 132 Participants |
| Race/Ethnicity, Customized Not Reported | 5 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 10 Participants | 21 Participants | 11 Participants |
| Race/Ethnicity, Customized White British | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White/Caucasian | 132 Participants | 269 Participants | 137 Participants |
| Race/Ethnicity, Customized White or Other | 1 Participants | 1 Participants | 0 Participants |
| Sex: Female, Male Female | 104 Participants | 222 Participants | 118 Participants |
| Sex: Female, Male Male | 50 Participants | 86 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 97 / 152 | 79 / 154 | 176 / 306 | 54 / 77 |
| other Total, other adverse events | 151 / 152 | 154 / 154 | 305 / 306 | 57 / 77 |
| serious Total, serious adverse events | 59 / 152 | 73 / 154 | 132 / 306 | 19 / 77 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS was defined as the time from the date of randomization to the date of the first documented disease progression (PD), according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by blinded independent central review committee (BICR), or death due to any cause, whichever occurred first. PD: progression of a target or non-target lesion or presence of a new lesion.
Time frame: up to 33.9 months
Population: Full Analysis Set: all randomized participants. Participants were analyzed according to the treatment and strata they had been assigned during randomization. Median PFS time was estimated using the Kaplan-Meier method. The confidence interval for median PFS time was calculated using the method of Brookmeyer and Crowley.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Retifanlimab 500 mg Q4W + Chemotherapy | Progression-free Survival (PFS) | 9.3 months |
| Placebo + Chemotherapy | Progression-free Survival (PFS) | 7.4 months |
p-value: 0.000695% CI: [0.47, 0.84]stratified log-rank test
Secondary
AUC of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel
AUC was defined as the area under the serum concentration versus time curve.
Time frame: preinfusion on Day 1 of Cycles 1, 2, 4, 6, 8, and 12; immediately after infusion on Day 1 of Cycles 1 and 4
Population: PK Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Retifanlimab 500 mg Q4W + Chemotherapy | AUC of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel | 2490 day x mg/L | Geometric Coefficient of Variation 40.1 |
Secondary
Cmax of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel
Cmax was defined as the maximum observed plasma concentration of retifanlimab.
Time frame: preinfusion on Day 1 of Cycles 1, 2, 4, 6, 8, and 12; immediately after infusion on Day 1 of Cycles 1 and 4
Population: Pharmacokinetic (PK) Evaluable Population: all participants who received at least 1 dose of study treatment and provided at least 1 postdose plasma sample
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Retifanlimab 500 mg Q4W + Chemotherapy | Cmax of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel | 209 milligrams per liter (mg/L) | Geometric Coefficient of Variation 27.9 |
Secondary
Cmin of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel
Cmin was defined as the minimum observed plasma concentration of retifanlimab.
Time frame: preinfusion on Day 1 of Cycles 1, 2, 4, 6, 8, and 12; immediately after infusion on Day 1 of Cycles 1 and 4
Population: PK Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Retifanlimab 500 mg Q4W + Chemotherapy | Cmin of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel | 49.5 mg/L | Geometric Coefficient of Variation 59.4 |
Secondary
Disease Control Rate (DCR)
DCR was defined as the percentage of participants maintaining either a confirmed overall response of CR or PR or stable disease (SD) at any post-Baseline visit before the first PD or new anticancer therapy, according to RECIST v1.1 as determined by BICR. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion. SD: no change in target lesions to qualify for CR, PR, or PD.
Time frame: up to 445 days
Secondary
Duration of Response (DOR)
DOR was defined as the time from the first documented response (CR or PR) determined by BICR to the time of first documented disease progression per RECIST v1.1 or death due to any cause. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 mm. PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions. PD: progression of a target or non-target lesion or presence of a new lesion.
Time frame: up to 32.1 months
Secondary
Number of Participants With Any TEAE During the Open-label Monotherapy Period
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as any AEs either reported for the first time or the worsening of a pre-existing events after the first dose of study treatment and within 90 days of the last administration of retifanlimab/placebo, or within 30 days of the last chemotherapy. AEs that occurred after new anticancer therapy were be excluded.
Time frame: up 457 days
Secondary
Number of Participants With Any TEAE Leading to Discontinuation of Study Drug During the Open-label Monotherapy Period
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as any AEs either reported for the first time or the worsening of a pre-existing events after the first dose of study treatment and within 90 days of the last administration of retifanlimab/placebo, or within 30 days of the last chemotherapy. AEs that occurred after new anticancer therapy were be excluded.
Time frame: up 457 days
Secondary
Number of Participants With Any TEAE Leading to Discontinuation of Study Drug During the Randomized Period
An AE was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as any AEs either reported for the first time or the worsening of a pre-existing events after the first dose of study treatment and within 90 days of the last administration of retifanlimab/placebo, or within 30 days of the last chemotherapy. AEs that occurred after new anticancer therapy were be excluded.
Time frame: up to 535 days
Population: Safety Population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Retifanlimab 500 mg Q4W + Chemotherapy | Number of Participants With Any TEAE Leading to Discontinuation of Study Drug During the Randomized Period | 17 Participants |
| Placebo + Chemotherapy | Number of Participants With Any TEAE Leading to Discontinuation of Study Drug During the Randomized Period | 4 Participants |
Secondary
Number of Participants With Any Treatment-emergent Adverse Event (TEAE ) During the Randomized Period
An adverse event (AE) was defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. An AE could therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. TEAEs were defined as any AEs either reported for the first time or the worsening of a pre-existing events after the first dose of study treatment and within 90 days of the last administration of retifanlimab/placebo, or within 30 days of the last chemotherapy. AEs that occurred after new anticancer therapy were be excluded.
Time frame: up to 535 days
Population: Safety Population: all randomized participants who received at least 1 dose of study treatment. Treatment groups for this population were determined according to the actual treatment the participant received regardless of treatment assignment at randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Retifanlimab 500 mg Q4W + Chemotherapy | Number of Participants With Any Treatment-emergent Adverse Event (TEAE ) During the Randomized Period | 154 Participants |
| Placebo + Chemotherapy | Number of Participants With Any Treatment-emergent Adverse Event (TEAE ) During the Randomized Period | 152 Participants |
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants with a CR or PR at any post-Baseline visit before the first PD or new anticancer therapy, according to RECIST v1.1 as determined by BICR. CR: disappearance of all target and non-target lesions and no appearance of any new lesions. Any pathological lymph nodes (whether target or non-target) must have a reduction in the short axis to \<10 millimeters (mm). PR: at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference the baseline sum diameters, no new lesions, and no progression of non-target lesions.
Time frame: up to 445 days
Secondary
Overall Survival
Overall survival was defined as the time from the date of randomization until the date of death due to any cause.
Time frame: up to 40.4 months
Secondary
Tmax of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel
tmax was defined as the time to the maximum serum concentration of retifanlimab.
Time frame: preinfusion on Day 1 of Cycles 1, 2, 4, 6, 8, and 12; immediately after infusion on Day 1 of Cycles 1 and 4
Population: PK Evaluable Population
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Retifanlimab 500 mg Q4W + Chemotherapy | Tmax of Retifanlimab at Steady State When Administered With Carboplatin-paclitaxel | 0.720 hours | Geometric Coefficient of Variation 35.8 |