Targeted Therapy and Avelumab in Merkel Cell Carcinoma (GoTHAM)

• ClinicalTrials.gov Identifier: NCT04261855
• Recruitment Status: Recruiting
• First Posted: February 10, 2020
• Last Update Posted: November 22, 2023
• Sponsor: Melanoma and Skin Cancer Trials Limited
• Information provided by (Responsible Party): Melanoma and Skin Cancer Trials Limited

Tracking Information

• First Submitted Date: February 6, 2020
• First Posted Date: February 10, 2020
• Last Update Posted Date: November 22, 2023
• Actual Study Start Date: October 8, 2020
• Estimated Primary Completion Date: July 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 6, 2020)

Progression Free Survival (PFS) at 12 months [ Time Frame: 3 years ]

To evaluate the anti-tumour activity as reflected by PFS rate at 12 months. PFS is defined as the time from treatment initiation until the first date of documented radiographic progression or death due to any cause, whichever occurs first. The radiographic progression will be assessed by the Investigator according to RECIST v1.1.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 6, 2020)

• Progression Free Survival (PFS) at 24 months [ Time Frame: 4 years ]
  Time to disease progression including rate at specific landmark timepoint of 24 months.
• Overall Survival (OS) at 12 and 24 months [ Time Frame: 4 years ]
  OS rates at specific landmark timepoints of 12 and 24 months. OS is defined as the time from treatment initiation to the date of death due to any cause.
• Best Objective Response Rate (ORR) according to RECIST v1.1 [ Time Frame: 4 years ]
  To evaluate best ORR according to response evaluation criteria in solid tumours version 1.1 (RECIST v1.1). ORR is defined as PR or CR at any stage from time of treatment initiation according to RECIST v1.1.
• The safety and tolerability of 177Lu-DOTATATE or EBRT in combination with avelumab. [ Time Frame: 4 years ]
  Rate of treatment-related adverse events (AEs). Safety will be measured by serious adverse events (SAEs) and AEs assessed using the NCI CTCAE v5.0.
• Rate of treatment discontinuation due to toxicity [ Time Frame: 4 years ]
  This is defined as the proportion of patients who discontinue with treatment due to treatment-related toxicity.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Targeted Therapy and Avelumab in Merkel Cell Carcinoma
• Official Title: A Phase Ib/II Study of Combination Avelumab With Peptide Receptor Radionuclide Therapy or Conventional Fractionated Radiotherapy in Patients With Metastatic Merkel Cell Carcinoma
• Brief Summary: 10.17 GoTHAM is intended as a signal-seeking, biomarker, phase Ib/II study that will evaluate the safety and anti-tumour activities of the novel combination of avelumab with 177-Lu-DOTATATE (a type of peptide receptor radionuclide therapy; PRRT) or external beam radiation therapy (EBRT) in patients with metastatic Merkel cell carcinoma (mMCC).

Detailed Description

Despite recent advances with immune checkpoint inhibitors, such as avelumab which has changed the treatment landscape for metastatic Merkel Cell Carcinoma (mMCC), many mMCC patients who attained an initial response exhibit acquired resistance within 1 year. Therefore, novel treatment combinations are needed to improve patient outcome. MCC is an exquisitely radiosensitive tumour and there is emerging data supporting the role of radiation in inducing immunogenic cell death and therefore potentially improving the anti-tumour efficacy when combined with immune checkpoint inhibitors. Peptide receptor radionuclide therapy (PRRT) is used in first-line treatment for neuroendocrine tumours (NETs), by delivering radiation to somatostatin receptor (SSTR) expressing tumour cells. Most NETs, including MCC, express SSTR. Therefore, MCC tumours are ideal candidates for PRRT, and immune checkpoint inhibitor combination approaches with PRRT are highly attractive.

The GoTHAM trial is intended as a signal-seeking and biomarker study. It is designed as a prospective, open-labelled, multi-institutional, two-arm, phase Ib/II trial that will evaluate the safety and anti-tumour activity of 177Lu-DOTA-octreotate (LuTate) or external beam radiation therapy (EBRT) in combination with avelumab in patients with mMCC. The primary objective is to evaluate the anti-tumour activity as reflected by PFS rate at 12 months.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Merkel Cell Carcinoma

Intervention

• Drug: Avelumab
  All patients will receive avelumab intravenously (IV) at 10 mg/kg every 2 weeks for 24 months or until unacceptable toxicity or evidence of disease progression
  Other Names:

  • Bavencio
  • Anti-PD-L1
• Radiation: External Beam Radiation Therapy (EBRT)
  Patients allocated to Arm A will receive EBRT on 2 occasions, 8-10 weeks apart
  Other Name: Radiotherapy
• Radiation: Lutetium-177 (177Lu)-DOTATATE
  Patients allocated to Arm B will receive 177-Lu-DOTATATE treatment on 2 occasions, 8-10 weeks apart
  Other Names:

  • Peptide Receptor Radionuclide Therapy (PRRT)
  • Lutathera

Study Arms

• Experimental: Arm A
  Avelumab plus External Beam Radiation Therapy (EBRT)
  Interventions:

  • Drug: Avelumab
  • Radiation: External Beam Radiation Therapy (EBRT)
• Experimental: Arm B
  Avelumab plus Lutetium-177 (177Lu)-DOTATATE
  Interventions:

  • Drug: Avelumab
  • Radiation: Lutetium-177 (177Lu)-DOTATATE

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 13, 2023): 38
• Original Estimated Enrollment (submitted: February 6, 2020): 65
• Estimated Study Completion Date: July 2027
• Estimated Primary Completion Date: July 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Patient is 18 years of age or older and who has provided written informed consent.
• Patient has histologically confirmed metastatic MCC.
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 .
• Willing and able to comply with all study protocol requirements for the duration of the study.
• Patient must have measurable disease by CT or MRI per RECIST version 1.1 criteria.
• Patient is treatment naïve (no prior systemic therapy for unresectable or metastatic MCC). Note that prior chemotherapy is permitted in the adjuvant setting for loco-regional disease. Prior radiation is permitted for treatment of the primary or loco-regional disease.
• At least 2 weeks since the completion of prior therapy, including surgery or radiotherapy.
• Screening laboratory values, obtained within 14 days prior to registration/randomisation must meet the criteria specified in the protocol.
• Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception
• WOCBP must have a negative serum or urine pregnancy test within within 7 days prior to the start of avelumab treatment and should be performed every 4 weeks in line with other safety bloods or clinical reviews.
• Male patients who are sexually active with a WOCBP must use any contraceptive method with a failure rate of less than 1% per year.
• Patient must be agreeable to have archival tumour material collected

Exclusion Criteria:

• Patient is excluded if they have ever had any brain or leptomeningeal metastases.
• Prior exposure to immune checkpoint inhibitors (e.g. anti-CTLA-4, anti-PD-1/PD-L1/PD-L2, etc.) or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
• Prior exposure to 177Lu-DOTATATE.
• Prior malignancy within the previous 2 years, except for locally curable cancers that have been apparently cured (e.g. basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix, colon, bladder or breast).
• Life expectancy of 6 months or less.
• An active, known or suspected autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients are permitted to enrol if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
• Current use of immunosuppressive medication, with exceptions detailed in the protocol
• Prior organ transplantation, including allogeneic stem-cell transplantation.
• Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
• Positive test for hepatitis B virus (HBV) surface antigen and/or confirmatory hepatitis C virus (HCV) RNA (if anti-HCV antibody tested positive at Screening).
• Pregnant or breastfeeding.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration.
• Persisting toxicity related to prior therapy (NCI CTCAE v5.0 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on Investigator's judgement are acceptable.
• Known prior severe hypersensitivity to investigational product or any component in its formulations, including known hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v5.0 Grade 3).
• Patients with symptomatic or impending cord compression unless appropriately treated beforehand and clinically stable.
• Use of any live vaccines against infectious diseases (e.g., influenza, varicella, etc.) within 30 days of registration.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Melanoma and Skin Cancer Trials Coordinator; +61 3 9903 9022; gotham@masc.org.au

• Listed Location Countries: Australia

Administrative Information

• NCT Number: NCT04261855
• Other Study ID Numbers: 10.17
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Melanoma and Skin Cancer Trials Limited
• Original Responsible Party: Same as current
• Current Study Sponsor: Melanoma and Skin Cancer Trials Limited
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Chair: Shahneen Sandhu, MBBS, FRACP; Peter MacCallum Cancer Centre, Australia

• PRS Account: Melanoma and Skin Cancer Trials Limited
• Verification Date: February 2023