Colorectal Cancer Metastatic
Conditions
Brief summary
The primary goal of this study is to characterize the safety, tolerability, and maximum tolerated dose (MTD) of MGD007 when combined with MGA012. Pharmacokinetics (PK), immunogenicity, pharmacodynamics (PD), and the anti-tumor activity of the combination of MGD007 and MGA012 will also be assessed.
Detailed description
This study is an open-label, Phase 1b/2, dose escalation and cohort expansion study designed to characterize the safety, tolerability, PK, PD, immunogenicity, and preliminary antitumor activity of MGD007 and MGA012, administered in combination by IV infusion, in patients with histologically proven, relapsed/refractory metastatic colorectal carcinoma, irrespective of the KRAS and MMR status of their tumors. The study consists of a Dose Escalation Phase to determine the MTD or Maximum Administered Dose (MAD; if no MTD is defined) of the combination, followed by a Cohort Expansion Phase to further define the safety and initial antitumor activity of the combination with the doses established in the Dose Escalation Phase.
Interventions
BIOLOGICALMGD007 + MGA012
MGD007 and MGA012 are administered by IV infusion.
Sponsors
MacroGenics
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
* Histologically proven, relapsed/refractory metastatic colorectal cancer * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Measurable disease per RECIST 1.1 criteria * Participants in the Dose Escalation Phase must have had recurrence, progression or intolerance to standard therapy consisting of at least 2 prior standard regimens (containing a fluoropyrimidine plus a platinum analogue and/or irinotecan) for metastatic disease. Participants in the Cohort Expansion portion will be allowed to participate after 1 prior standard regimen. Those who are inappropriate candidates for or have refused treatment with these regimens are also eligible. No more than 5 prior therapies are permitted. Patients previously treated with MGD007 on Study Protocol CP-MGD007-01 and who did not develop antibodies to MGD007 while on the CP-MGD007-01 study, may be enrolled. Patients that were previously treated on CP-MGD007-01 will only be treated on this study once MTD/MAD has been defined. * Availability of sufficient tumor specimens to enable retrospective determination of gpA33, CD3, PD-1, and PD-L1 expression * 30 participants in the Cohort Expansion portion must have lesions that are accessible for paired biopsies with acceptable clinical risk in the judgment of the investigator.
Exclusion criteria
* Symptomatic central nervous system (CNS) metastases. No concurrent treatment for the CNS disease; no progression of CNS metastases on MRI or CT for at least 14 days after last day of prior therapy for the CNS metastases; no concurrent leptomeningeal disease or cord compression * History of known or suspected autoimmune disease with certain exceptions * History of prior allogeneic bone marrow, stem-cell, or solid organ transplantation. * Major surgery, systemic anti-neoplastic therapy, or investigational therapy within 4 weeks * Radiation therapy within 2 weeks * Systemic corticosteroids (≥ 10 mg per day prednisone or equivalent) or other immune suppressive drugs within the 14 days * History of Grade 3 or greater drug-related diarrhea/colitis during treatment with checkpoint inhibitors including anti-LAG-3, anti-PD-1, anti PD-L1, or anti-CTLA-4 antibodies * Clinically significant cardiovascular disease; gastrointestinal disorders; pulmonary compromise; viral, bacterial, or systemic fungal infections * History of positive testing for human immunodeficiency virus or history of acquired immune deficiency syndrome * History of hepatitis B or hepatitis C infection or known positive test for hepatitis B surface antigen, hepatitis B core antigen, or hepatitis C polymerase chain reaction.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | Up to approximately 12 weeks | Adverse Events, Serious Adverse Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peak Plasma Concentration | 7 weeks | PK of MGD007 and MGA012 in combination |
| Number of Participants That Develop Anti-drug Antibodies | 1 year | Proportion of patients who develop anti-MGD007/MGA012 antibodies, immunogenicity |
| The Number of Participants With Response Based on the Change in Tumor Volume | Every 8 weeks | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and immune related RECIST criteria: number of patients with either complete response (CR) or partial response (PR) will determine the Overall Response Rate (ORR) |
Countries
United States
Participant flow
Recruitment details
Patients were recruited at 6 academic/oncology centers experienced in the conduct of clinical trials.
Participants by arm
| Arm | Count |
|---|---|
| Dose Level 1 0.4 mcg/kg MGD007 administered by intravenous (IV) infusion once per week in 8-week cycles, plus 3 mg/kg MGA012 administered by IV infusion once every 2 weeks. | 5 |
| Dose Level 2 0.6 mcg/kg MGD007 administered by intravenous (IV) infusion once per week in 8-week cycles, plus 3 mg/kg MGA012 administered by IV infusion once every 2 weeks. | 3 |
| Dose Level 3 0.8 mcg/kg MGD007 administered by intravenous (IV) infusion once per week in 8-week cycles, plus 3 mg/kg MGA012 administered by IV infusion once every 2 weeks. | 28 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Death | 4 | 0 | 14 |
| Overall Study | Study Terminated | 1 | 3 | 11 |
Baseline characteristics
| Characteristic | Dose Level 1 | Dose Level 2 | Dose Level 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 53.4 Years STANDARD_DEVIATION 5.13 | 46.3 Years STANDARD_DEVIATION 2.89 | 55.5 Years STANDARD_DEVIATION 7.54 | 54.5 Years STANDARD_DEVIATION 7.36 |
| ECOG Performance Status ECOG Performance Status 0 (Fully active without restriction) | 2 Participants | 1 Participants | 15 Participants | 18 Participants |
| ECOG Performance Status ECOG Performance Status 1 (restricted in physically strenuous activity, but ambulatory) | 3 Participants | 2 Participants | 13 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 2 Participants | 3 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 | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 5 Participants | 2 Participants | 25 Participants | 32 Participants |
| Region of Enrollment United States | 5 participants | 3 participants | 28 participants | 36 participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 13 Participants | 16 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 15 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 4 / 5 | 0 / 3 | 14 / 28 |
| other Total, other adverse events | 5 / 5 | 3 / 3 | 28 / 28 |
| serious Total, serious adverse events | 1 / 5 | 1 / 3 | 14 / 28 |
Outcome results
Primary
Number of Participants With Adverse Events
Adverse Events, Serious Adverse Events
Time frame: Up to approximately 12 weeks
Population: All patients who received at least one dose of study drug and reporting at least one adverse event
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Level 1 | Number of Participants With Adverse Events | 5 Participants |
| Dose Level 2 | Number of Participants With Adverse Events | 3 Participants |
| Dose Level 3 | Number of Participants With Adverse Events | 28 Participants |
Secondary
Number of Participants That Develop Anti-drug Antibodies
Proportion of patients who develop anti-MGD007/MGA012 antibodies, immunogenicity
Time frame: 1 year
Population: ADA assays were not performed since the Sponsor has decided not to continue clinical development of MGD007.
Secondary
Peak Plasma Concentration
PK of MGD007 and MGA012 in combination
Time frame: 7 weeks
Population: PK assays were not performed since the Sponsor has decided not to continue clinical development of MGD007.
Secondary
The Number of Participants With Response Based on the Change in Tumor Volume
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) and immune related RECIST criteria: number of patients with either complete response (CR) or partial response (PR) will determine the Overall Response Rate (ORR)
Time frame: Every 8 weeks
Population: Response evaluable population
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Level 1 | The Number of Participants With Response Based on the Change in Tumor Volume | Stable Disease | 0 Participants |
| Dose Level 1 | The Number of Participants With Response Based on the Change in Tumor Volume | Progressive Disease | 5 Participants |
| Dose Level 2 | The Number of Participants With Response Based on the Change in Tumor Volume | Stable Disease | 1 Participants |
| Dose Level 2 | The Number of Participants With Response Based on the Change in Tumor Volume | Progressive Disease | 2 Participants |
| Dose Level 3 | The Number of Participants With Response Based on the Change in Tumor Volume | Stable Disease | 10 Participants |
| Dose Level 3 | The Number of Participants With Response Based on the Change in Tumor Volume | Progressive Disease | 14 Participants |