Adenoid Cystic Carcinoma
Conditions
Brief summary
This is a Phase 2, non comparative, open label, multicenter study of AL101 in patients with recurrent or metastatic ACC who harbor NOTCH 1,2,3,4 activating mutations.
Detailed description
This is a Phase 2, non-comparative, open-label, multicenter study of AL101 in patients with recurrent or metastatic ACC who harbor NOTCH 1,2,3,4 activating mutations. The study includes 2 cohorts, ran in a sequential fashion: Cohort 1 - AL101 4 mg once weekly (QW) intravenously (IV) Cohort 2 - AL101 6 mg QW IV
Interventions
DRUGAL101
AL101 is a small-molecule that inhibits gamma secretase, an enzyme which plays a key role in the activation of the Notch signaling pathway by releasing the Notch intracellular domain (NICD) of all four Notch receptors from the membrane. In patients with aberrant Notch signaling, AL101 may inhibit Notch signaling and potentially impede tumor growth.The drug is administered intravenously
Sponsors
Ayala Pharmaceuticals, Inc,
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open label
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Confirmed Adenoid Cystic Carcinoma with known NOTCH 1/2/3/4 activating mutation that is recurrent or metastatic, not amenable to potentially curative surgery or radiotherapy. 2. Evidence of radiographic or clinical disease progression within 6-months of signing informed consent; newly diagnosed metastatic patients will be allowed. 3. Patients must have Formalin-fixed, Paraffin-embedded tissue available . 4. Must have at least 1 target lesion that is measurable for patients with nodal or visceral metastasis.
Exclusion criteria
1. Diagnosed with a malignancy other than ACC in the past 2 years. 2. Uncontrolled, Active Infection 3. Gastrointestinal (GI) disease with increased risk of diarrhea \[e.g. inflammatory bowel disease (IBD)\] 4. Symptomatic central nervous system (CNS) metastases. 5. Unstable or severe uncontrolled medical condition 6. Eastern Cooperative Oncology Group (ECOG) performance status ≥2. 7. Abnormal organ and marrow function
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | 3 years and 7 months | ORR is defined as partial response (PR) + complete response (CR) as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for target lesions assessed by MRI. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Response Rate (CBR) | 3 years and 7 months | Clinical benefit response rate (CBR) is defined as complete response (CR) + partial response (PR) + stable disease (SD) by investigator review based on RECIST v1.1 for target lesions assessed by MRI. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage (at least 30%) to qualify for PR nor sufficient increase (more than 20%) to qualify for PD, taking as reference the smallest sum diameters. |
| Overall Survival | 3 years and 5 months | Overall survival is defined at the time from first infusion of investigational product to death due to any cause. Subjects with no documentation of death were censored at the last known date known to be alive. |
Countries
Canada, France, Israel, Netherlands, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - AL101 4mg AL101 4 mg once weekly (QW) intravenously (IV) | 45 |
| Cohort 2 - AL101 6mg AL101 6 mg once weekly (QW) intravenously (IV) | 42 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 41 | 26 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Sponsor decision | 1 | 7 |
| Overall Study | Withdrawal by Subject | 2 | 8 |
Baseline characteristics
| Characteristic | Cohort 1 - AL101 4mg | Total | Cohort 2 - AL101 6mg |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 25 Participants | 15 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 62 Participants | 27 Participants |
| Age, Continuous | 50 Years | 56 Years | 59 Years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 14 Participants | 6 Participants |
| Race (NIH/OMB) White | 31 Participants | 64 Participants | 33 Participants |
| Region of Enrollment Canada | 3 participants | 4 participants | 1 participants |
| Region of Enrollment France | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Israel | 0 participants | 3 participants | 3 participants |
| Region of Enrollment Netherlands | 0 participants | 4 participants | 4 participants |
| Region of Enrollment Spain | 0 participants | 3 participants | 3 participants |
| Region of Enrollment United Kingdom | 3 participants | 8 participants | 5 participants |
| Region of Enrollment United States | 38 participants | 61 participants | 23 participants |
| Sex: Female, Male Female | 25 Participants | 43 Participants | 18 Participants |
| Sex: Female, Male Male | 20 Participants | 44 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 41 / 45 | 26 / 42 |
| other Total, other adverse events | 45 / 45 | 42 / 42 |
| serious Total, serious adverse events | 23 / 45 | 26 / 42 |
Outcome results
Primary
Overall Response Rate (ORR)
ORR is defined as partial response (PR) + complete response (CR) as assessed by the investigator based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 for target lesions assessed by MRI. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Time frame: 3 years and 7 months
Population: Efficacy evaluable analysis set includes all subjects who receive at least one complete infusion of study drug, have measurable disease at baseline per RECIST v1.1 or modified MDA criteria for bone-exclusive disease and have at least one post-baseline on-study assessment of tumor response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 - AL101 4mg | Overall Response Rate (ORR) | 3 Participants |
| Cohort 2 - AL101 6mg | Overall Response Rate (ORR) | 2 Participants |
Secondary
Clinical Benefit Response Rate (CBR)
Clinical benefit response rate (CBR) is defined as complete response (CR) + partial response (PR) + stable disease (SD) by investigator review based on RECIST v1.1 for target lesions assessed by MRI. Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable Disease (SD): Neither sufficient shrinkage (at least 30%) to qualify for PR nor sufficient increase (more than 20%) to qualify for PD, taking as reference the smallest sum diameters.
Time frame: 3 years and 7 months
Population: Efficacy evaluable analysis set includes all subjects who receive at least one complete infusion of study drug, have measurable disease at baseline per RECIST v1.1 or modified MDA criteria for bone-exclusive disease and have at least one post-baseline on-study assessment of tumor response.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 - AL101 4mg | Clinical Benefit Response Rate (CBR) | 28 Participants |
| Cohort 2 - AL101 6mg | Clinical Benefit Response Rate (CBR) | 24 Participants |
Secondary
Overall Survival
Overall survival is defined at the time from first infusion of investigational product to death due to any cause. Subjects with no documentation of death were censored at the last known date known to be alive.
Time frame: 3 years and 5 months
Population: Efficacy evaluable analysis set includes all subjects who receive at least one complete infusion of study drug, have measurable disease at baseline per RECIST v1.1 or modified MDA criteria for bone-exclusive disease and have at least one post-baseline on-study assessment of tumor response.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - AL101 4mg | Overall Survival | 9.3 months |
| Cohort 2 - AL101 6mg | Overall Survival | 9.4 months |