M7824 in Patients With Metastatic Colorectal Cancer or With Advanced Solid Tumors With Microsatellite Instability

Metastatic Malignant Solid Neoplasm Clinical Trial

Official title: A Phase Ib/II Trial of M7824 in Solid Tumors With Microsatellite Instability With Consensus Molecular Subtype 4 Metastatic Colorectal Cancer in Combination With Radiation, or in Colorectal Cancer Patients With Detectable Circulating Tumor DNA Following Definitive Therapy

Status Active, not recruiting

Clinical Trial Summary

This phase Ib/II trial studies how well anti-PD-L1/TGFbetaRII fusion protein M7824 (M7824) works in treating patients with colorectal cancer (or with other solid tumors with microsatellite instability) that has spread to other places in the body or cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as M7824, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Clinical Trial Description

PRIMARY OBJECTIVES:

-Objective response rate (ORR) in microsatellite instability-high (MSI-H) mCRC patients who have progressed on immune checkpoint blockade therapy (Cohort A).

OR

-ORR in patients with treatment-refractory, consensus molecular subtype 4 (CMS4) mCRC patients coadmnistered SBRT (Cohort B).

OR

• ORR in patients with MSI-H non CRC solid tumors who have progressed on immune checkpoint blockade therapy (Cohort C) OR

• Clearance of ctDNA in ctDNA(+) patients with resected mCRC following completion of standard-of-care therapy (Cohort D).

SECONDARY OBJECTIVES:

To estimate progression-free survival (PFS) for M7824 in patients with:

-MSI-H mCRC whose disease has progressed on prior immune checkpoint blockade therapy (Cohort A).

OR

-Treatment-refractory, CMS4 mCRC coadministered SBRT (Cohort B). While SBRT is preferred, IMRT or 3D conformal techniques may be utilized at the discretion of the treating radiation oncologist depending on the dose to surrounding normal tissues. Patient will receive a total dose of 24Gy over three days with one of the following modalities, at the discretion of the treating radiation oncologist: SBRT, IMRT and 3D conformal.

OR o MSI-H LA/UR/metastatic non-CRC solid tumors with prior progression on an immune checkpoint blockade therapy (Cohort C).

To estimate overall survival (OS) for M7824 in patients with:

o MSI-H mCRC who are refractory to prior immune checkpoint blockade therapy (Cohort A).

OR o Treatment-refractory, CMS4 mCRC coadministered SBRT (Cohort B). While SBRT is preferred, IMRT or 3D conformal techniques may be utilized at the discretion of the treating radiation oncologist depending on the dose to surrounding normal tissues. Patient will receive a total dose of 24Gy over three days with one of the following modalities, at the discretion of the treating radiation oncologist: SBRT, IMRT and 3D conformal.

OR

• MSI-H LA/UR/metastatic non-CRC solid tumors with prior progression on an immune checkpoint blockade therapy (Cohort C) OR

• ctDNA(+) resected mCRC following completion of standard-of-care therapy (Cohort D).

To estimate disease-free survival (DFS) in patients with resected mCRC following standard-of-care treatment (cohort D).

To evaluate safety and tolerability of treatment with M7824 in patients with:

o MSI-H mCRC who are refractory to prior immune checkpoint blockade therapy (Cohort A).

OR

• Treatment-refractory, CMS4 mCRC (Cohort B) OR

• MSI-H LA/UR/metastatic non-CRC solid tumors with prior progression on an immune checkpoint blockade therapy (Cohort C) OR

• ctDNA(+) resected mCRC following completion of standard-of-care therapy (Cohort D).

EXPLORATORY OBJECTIVES:

1. To evaluate intratumoral pharmacodynamic changes in immune populations using paired biopsies from patients with MSI-H solid tumors (Cohorts A and C) or CMS4 mCRC treated with M7824 and SBRT (Cohort B). While SBRT is preferred, IMRT or 3D conformal techniques may be utilized at the discretion of the treating radiation oncologist depending on the dose to surrounding normal tissues. Patient will receive a total dose of 24Gy over three days with one of the following modalities, at the discretion of the treating radiation oncologist: SBRT, IMRT and 3D conformal.

2. To characterize circulating immune cell populations and cytokine profiles in tumor and circulation following treatment with M7824.

3. To describe changes in levels of TGF-β following treatment with M7824.

4. To correlate the presence of microsatellite instability with CMS1 profile.

5. To correlate MSI-H and CMS4 to CpG island methylator phenotype (CIMP) status, KRAS and BRAF mutation status.

6. To quantify correlation with CMS4 and immune populations within tumor infiltrate.

7. To correlate anti-tumor response to M7824 with PD-L1 expression.

8. To conduct RNAseq, RNA Scope, WES targeted sequencing and tissue IO gene expression by Nanostring.

9. To evaluate novel markers in blood by liquid biopsy including, but not limited to, circulating-free DNA (cfDNA), exosomes, and circulating tumor cells (CTC).

10. To describe changes in microbiome profiling upon treatment with M7824 (with or without radiation).

OUTLINE:

For cohorts A, B, and C, patients receive M7824 intravenously (IV) over 1 hour on days 1 and

15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

For cohort D, patients receive M7824 intravenously (IV) over 1 hour on days 1 and 15 for a total of six treatments.

After completion of study treatment, patients are followed up at 28 days. ;

Related Conditions & MeSH terms

• Adenocarcinoma
• Colon Adenocarcinoma
• Colonic Neoplasms
• Colorectal Neoplasms
• High-Frequency Microsatellite Instability
• Metastatic Malignant Solid Neoplasm
• Microsatellite Instability
• Rectal Adenocarcinoma
• Rectal Neoplasms
• Refractory Colorectal Carcinoma
• Stage IV Colon Cancer AJCC v8
• Stage IV Rectal Cancer AJCC v8
• Stage IVA Colon Cancer AJCC v8
• Stage IVA Rectal Cancer AJCC v8
• Stage IVB Colon Cancer AJCC v8
• Stage IVB Rectal Cancer AJCC v8

• NCT number: NCT03436563
• Study type: Interventional
• Source: M.D. Anderson Cancer Center
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: March 7, 2018
• Completion date: August 2023