Microsatellite Stable Metastatic Colorectal Cancer
Conditions
Keywords
evorpacept (ALX148), Cetuximab, Pembrolizumab, CRC, colorectal cancer, microsatellite stable, MSS, CD47, SIRPa
Brief summary
This Phase 2 clinical study will evaluate evorpacept (ALX148) in combination with cetuximab and pembrolizumab for refractory microsatellite stable metastatic colorectal cancer
Detailed description
This is an open-label, multi-center, single-arm phase II clinical trial (with safety run-in) evaluating the combination of evorpacept (ALX148), cetuximab, and pembrolizumab in patients with metastatic microsatellite stable colorectal cancer who have progressed on at least 2 lines of systemic therapy. A subset of patients will undergo study-related biopsies. There will be a safety run-in stage followed by a dose expansion stage. Patients in both stages will continue to receive study therapy until disease progression according to RECIST v1.1.
Interventions
Sponsors
University of Colorado, Denver
ALX Oncology Inc.
Merck Sharp & Dohme LLC
Eli Lilly and Company
Criterium, Inc.
Academic GI Cancer Consortium (AGICC)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
To be eligible to participate in this study, an individual must meet all of the following criteria at screening (any assessments included in the Schedule of Events \[Section 1.3\] on Cycle 1 Day 1 must also continue to be met for the patient to remain eligible): 1. Provision to sign and date the consent form. 2. Able to comply with all study procedures and be available for the duration of the study in the Investigator's judgment. 3. Age ≥ 18 years on the day of signing informed consent 4. If in Cohort A, the patient must state willingness to undergo pre- and post-treatment biopsies. According to the Investigator's judgement, the planned biopsies should not expose the patient to substantially increased risk of complications. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Histologically confirmed unresectable metastatic colorectal adenocarcinoma. * All primary tumor locations are allowed * Measurement of EGFR expression by immunohistochemistry is not required 7. Progression on at least two prior lines of therapy for unresectable metastatic colorectal adenocarcinoma. * A patient who progressed on a single line of therapy including a fluoropyrimidine, oxaliplatin, and irinotecan for unresectable metastatic colorectal adenocarcinoma (e.g., FOLFIRINOX or FOLFOXIRI) is eligible. * Previous administration of anti-EGFR drugs does not impact eligibility, except as listed in Exclusion Criterion #15. 8. Microsatellite stable or proficient mismatch repair status documented (only one of these criteria is needed, however if one criterion is met and one is not met then the patient is excluded) 9. Measurable disease, according to RECIST v1.1. Previously irradiated lesions are not considered measurable unless progression has been documented in the lesion. Note that lesions intended to be biopsied should not be target lesions. 10. Adequate hematologic and end organ function, defined by the following laboratory results: * ANC ≥ 1.5 × 109/L * Platelet count ≥ 100 × 109/L * Hemoglobin ≥ 9 g/dL without transfusion in the previous week * Serum bilirubin ≤ 1.5 x the upper limit of normal (ULN); patients with known Gilbert's disease may have a bilirubin ≤ 3.0 ×ULN * AST, ALT, and alkaline phosphatase (ALP) ≤ 3 × ULN with the following exceptions: * Patients with documented liver metastases: AST and/or ALT ≤ 5 ×ULN * Patients with documented liver or bone metastases: ALP ≤ 5×ULN * Creatinine clearance ≥ 50 mL/min as calculated using the Cockcroft-Gault formula or measured using a 24-hour urine collection * International normalized ratio (INR) OR prothrombin time (PT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as INR or PT is within expected or therapeutic range of intended use of anticoagulants * Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as aPTT is within expected or therapeutic range of intended use of anticoagulants 11. QTcF interval of ≤480 msec (Based upon value from the screening ECG). 12. Serum pregnancy test (for females of childbearing potential) negative at screening and at C1D1. A woman is considered fertile (woman of childbearing potential, "WOCBP") following menarche and until becoming post-menopausal unless permanently sterile. Women in the following categories are not considered WOCBP: * Premenarchal * Premenopauseal female with one of the following: documented hysterectomy, documented bilateral salpingectomy, documented bilateral oophorectomy (note: documentation can come from the site personnel's review of the participant's medical records, medical examination, or medical history interview) * Postmenopausal female. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required. Females on HRT and whose menopausal status is in doubt will be required to use one of the non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrollment. Female participants of childbearing potential are eligible to participate if they agree to correctly use one of the following forms of highly effective method of contraception with a failure rate of \<1% per year when used consistently and correctly during the treatment period and for at least 180 days after the last study treatment. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Use should be consistent with local regulations regarding the use of contraceptive methods for participants of clinical studies. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable hormonal contraceptives are limited to those which inhibit ovulation. * Progestogen- only contraceptive implant * Intrauterine hormone-releasing system * Intrauterine device (IUD) * Bilateral tubal occlusion * Vasectomized partner. A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. * Sexual abstinence. Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. * Combined (estrogen- and progestogen- containing) hormonal contraception, including oral, intravaginal, transdermal, or injectable * Progestogen-only hormonal contraception, including oral or injectable 13. For men: Male participants with female partners of childbearing potential are eligible to participate if they agree to one of the following during the treatment period and for at least 180 days after the last dose of study treatment as defined below. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Men must also agree to refrain from donating sperm following during the treatment period and for at least 180 days after the last dose of study treatment. * Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent * Use a male condom plus partner use of a contraceptive method with a failure rate of \<1% per year as described in Inclusion Criteria #12 when having penile-vaginal intercourse with a woman of childbearing potential who is not currently pregnant. * Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penile penetration. Inclusion Criteria: An individual who meets any of the following criteria will be excluded from participation in this study: Cancer-related
Exclusion criteria
1. Patients with known MSI-high status or known mismatch repair deficiency (dMMR) 2. Patients in whom both mismatch repair and microsatellite stability status are unknown 3. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to Cycle 1 Day 1. 4. Systemic anti-cancer therapy within 4 weeks of starting study treatment (6 weeks for mitomycin C or nitrosureas). If systemic anti-cancer therapy was given within 4 weeks, patient may be included if 5 times the elimination half-life of the drug has passed. 5. Malignancies other than CRC within 3 years prior to Cycle 1 Day 1 with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year overall survival \> 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, and ductal carcinoma in situ treated surgically with curative intent). 6. Prior radiation therapy within 14 days prior to study Cycle 1 Day 1 and/or persistence of radiation-related adverse effects. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease. However, palliative radiation therapy (as long as it does not involve target lesions) is permitted on the study. 7. Prior allogeneic bone marrow transplantation or solid organ transplant for another malignancy in the past. 8. Spinal cord compression not definitively treated with surgery and/or radiation. 9. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures. 10. Uncontrolled tumor related pain. Patients who require narcotic pain medication during screening should be on a stable dose regimen for seven days prior to Cycle 1 Day 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | The duration of time during which tumor assessments were performed for each individual patient. Per protocol, assessments will continue until disease progression. The latest assessment was performed at Cycle 21, Day 15 (14.5 mo after informed consent) | A patient is considered to be an objective responder if their best overall response (BOR) of their follow-up tumor assessments was assessed to be complete response (CR) or partial response (PR) per RECIST v1.1. ORR is defined as the proportion of patients who were classified as objective responders. |
| Determine the Recommended Dose (RD) of Evorpacept (ALX148) in Combination With Cetuximab and Pembrolizumab | During the safety run-in, each patient must have completed at least the 1st cycle (3 weeks) of treatment. | The recommended dose (RD) of evorpacept was determined by evaluating the totality of the first-cycle clinical data. Rules to determine the RD based on the number of patients experiencing a dose-limiting toxicity (DLT) were defined in the protocol. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | The duration of time during which tumor assessments were performed for each individual patient. Per protocol, assessments will continue until disease progression. The latest assessment was performed at Cycle 21, Day 15 (14.5 mo after informed consent). | A patient is classified as 'Disease Controlled' if their best overall response (BOR) of their follow-up tumor assessments was assessed to be complete response (CR), partial response (PR), or stable disease (SD) per RECIST v1.1. DCR is defined as the proportion of patients who were classified as 'Disease Controlled'. |
| Duration Of Response (DOR) | From date of 1st response (CR or PR) until either progression (PD or death) or censoring date | DOR is defined as the length of time (months) from the 1st response (CR or PR per RECIST v1.1) until either the first observation of progressive disease (PD) or death from any cause. Patients who did not experience PD or die are considered to be censored at the latest date they are confirmed to be alive, which is the most recent of their discontinuation date or latest follow-up date. This is a subgroup analysis, consisting of all patients who experienced response (CR or PR per RECIST v1.1) |
| Progression-Free Survival (PFS) | For each subject, from enrollment until the end of their months-to-progression (as defined above) | Months-to-Progression is defined as the length of time (in months) from enrollment until either the first observation of progressive disease (PD) using RECIST v1.1 or death from any cause. Patients who did not have PD or die will be considered to be censored at the latest date they are confirmed to be alive, which is the most recent of their discontinuation date or latest follow-up date. PFS is a survival analysis involving both the binary endpoint of whether or not each patient progressed or not (i.e. were censored), and the months-to-progression times for each patient. |
| Overall Survival (OS) | For each subject, from enrollment until the end of their months-to-death time (as defined above) | Months-to-death is defined as the number of months from enrollment until death from any cause. Subjects who did not die will be considered to be censored at the latest date they are confirmed to be alive, which is the most recent of their discontinuation date or latest follow-up date. OS is a survival analysis involving both the binary endpoint of whether or not each patient died or not, and the months-to-death times for each patient. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORWells Messersmith, MD
University of Colorado, Denver
Participant flow
Recruitment details
Pts with refractory MSS CRC were treated with triple therapy in a safety run-in (Stage 1) followed by expansion (Stage 2). Primary objectives were to determine recommended dose of evorpacept and objective response rate (vs historical control). Trial enrollment was terminated early due to safety concerns.
Pre-assignment details
Patients were eligible for this study if they were 18 years of age or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and had pMMR/MSS mCRC which had progressed on at least two prior lines of therapy in the metastatic setting (a prior single line of therapy for metastatic disease including a fluoropyrimidine, oxaliplatin, and irinotecan was allowed. Three (3) enrolled subjects did not start treatment, 2 due to the trial being halted, and 1 withdrew consent.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 6 / 9 | 1 / 4 |
| other Total, other adverse events | 3 / 3 | 9 / 9 | 4 / 4 |
| serious Total, serious adverse events | 2 / 3 | 5 / 9 | 4 / 4 |
Outcome results
None listed