Immunotherapy Combined With Y-90 and SBRT for Colorectal Liver Metastases

NCT03802747 | Withdrawn Phase 1 DMC FDA Drug

• 2 other identifiers: 18-0710.ccESR-17-13132
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This study is evaluating the combination of Y-90 radioembolization followed by SBRT with the immunotherapy drugs, durvalumab and tremelimumab, to improve disease control of liver metastases for patients with microsatellite stable colorectal cancer.

Conditions

Colorectal Cancer

Keywords

Liver Metastases; Phase 1; Durvalumab; Tremelimumab; Yttrium-90; Radioembolization; Stereotactic Body Radiation Therapy

Outcome Measures

Primary Outcomes (2)

• Incidence of Treatment Related Adverse Events

  Adverse events related to Y-90, SBRT, and durvalumab plus tremelimumab will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.

  Start of study to 3 months post treatment completion, up to 5 years

• Dose-Limiting Toxicity of Y-90+SBRT in Combination with Dual Immune Checkpoint Blockade

  Defined as the rate of \>Grade 3 treatment-related adverse events during treatment or within 3 months of treatment completion.

  Start of study to 3 months post treatment completion, up to 5 years

Secondary Outcomes (7)

• Duration of Response (DoR)

  Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

• Progression Free Survival for Three Months (PFS)

  Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

• Overall Response Rate (ORR)

  Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

• Overall Survival for Two Years (OS)

  Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

• Liver Progression Free Survival for One Year (L-PFS)

  Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

Study Arms (2)

Y-90, SBRT, and Durvalumab Alone

EXPERIMENTAL

Six patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab.

Drug: Durvalumab; Drug: Y-90 Selective Internal Radiation Therapy (SIRT); Drug: Stereotactic Body Radiation Therapy (SBRT)

Y-90, SBRT, and Durvalumab + Tremelimumab

EXPERIMENTAL

Six patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab + Tremelimumab.

Drug: Durvalumab and Tremelimumab; Drug: Y-90 Selective Internal Radiation Therapy (SIRT); Drug: Stereotactic Body Radiation Therapy (SBRT)

Interventions

Durvalumab DRUG

Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity.

Y-90, SBRT, and Durvalumab Alone

Durvalumab and Tremelimumab DRUG

Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity. Tremelimumab will be dosed at 75 mg every 4 weeks (same day as durvalumab infusion) for a maximum of 4 doses.

Y-90, SBRT, and Durvalumab + Tremelimumab

Y-90 Selective Internal Radiation Therapy (SIRT) DRUG

Yttrium-90 microsphere therapy consists of resin beads loaded with Yttrium, a pure beta emitter with a 64.2 hour half-life. Radioembolization will be performed as standard of care therapy per current NCCN guidelines.

Y-90, SBRT, and Durvalumab + Tremelimumab; Y-90, SBRT, and Durvalumab Alone

Stereotactic Body Radiation Therapy (SBRT) DRUG

High-dose hypofractionated conformal external beam radiation therapy that is considered a standard of care. SBRT will also be considered for metastases that are persistent and/or progressive after Y-90 based on MR imaging and pathology from tissue biopsies.

Y-90, SBRT, and Durvalumab + Tremelimumab; Y-90, SBRT, and Durvalumab Alone

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologic or cytologic confirmation of metastatic microsatellite stable colorectal cancer
• Liver metastases not amenable to resection for which palliative Y-90 and SBRT is considered appropriate standard therapy
• Patients should have received at least one prior standard therapy for metastatic disease. Prior therapies should include regimens containing oxaliplatin and irinotecan in combination with a fluoropyrimidine if appropriate (e.g., FOLFOX and FOLFIRI or their variants) unless contraindicated, not tolerated, or declined.
• Male or female, age 18 or older
• ECOG performance status of 0 or 1
• Body weight \>30 kg
• Life expectancy of greater than 6 months
• Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
• Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• Patients must have acceptable organ and marrow function as defined below:
• Hemoglobin ≥9.0 g/dL
• Absolute neutrophil count (ANC ≥1.0 x (\> 1000 per mm3))
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
• Total bilirubin : \< 2x upper limit of normal

You may not qualify if:

• Participation in another clinical study with an investigational drug during the last 4 weeks.
• Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
• Patients with Grade \>2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• History of allogenic organ transplantation.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
• Any chronic skin condition that does not require systemic therapy
• Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• Patients with celiac disease controlled by diet alone
• Prior therapy with an anti-PD-1 or anti-PD-L1, including durvalumab antibody within 6 months prior to enrollment and anti-CTLA4 (including tremelimumab)
• Prior abdominal radiotherapy

Sponsors & Collaborators

• University of Colorado, Denver: lead
• AstraZeneca: collaborator

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

durvalumab; tremelimumab; Radiosurgery

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Karyn Goodman, MD

  University of Colorado, Denver

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The first 6 patients will receive durvalumab alone with Y-90 and SBRT followed by 4 months of durvalumab. The next 6 patients will received durvalumab with Y-90 and SBRT followed by 4 months of durvalumab + tremelimumab.Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity. There will be no dose escalation. For patients who will receive both Durvalumab and Tremelimumab, the Tremelimumab will be dosed at 75 mg every 4 weeks (same day as durvalumab infusion) for a maximum of 4 doses. There will be no dose escalation.

Study Record Dates

• First Submitted: January 8, 2019
• First Posted: January 14, 2019
• Study Start: August 1, 2019
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2024
• Last Updated: December 9, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share