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.

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.

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.

Safety analysis population

Study Day 1 through study completion, average 36 days.

Treatment-emergent AEs were summarized by system organ class (SOC) and preferred term (PT), by relationship to study drugs, and by highest severity. For laboratory tests, number and percent of patients shifted from baseline to post-baseline maximum severity in CTCAE grade were summarized.