Targeted Therapy and Avelumab in Merkel Cell Carcinoma (GoTHAM)

A Phase Ib/II Study of Combination Avelumab With Peptide Receptor Radionuclide Therapy or Conventional Fractionated Radiotherapy in Patients With Metastatic Merkel Cell Carcinoma

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Merkel Cell Carcinoma
• Intervention / Treatment: Drug: Avelumab; Radiation: External Beam Radiation Therapy (EBRT); Radiation: Lutetium-177 (177Lu)-DOTATATE

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.

The LuTate arm of this study is now closed to recruitment.

• Study Type: Interventional
• Enrollment (Estimated): 19
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Coffs Harbour, New South Wales, Australia, 2450
      • Mid North Coast Cancer Institute - Coffs Harbour Health Campus
    • Gateshead, New South Wales, Australia, 2290
      • Lake Macquarie Private Hospital
    • Gosford, New South Wales, Australia, 2250
      • Gosford Hospital
    • Hamlyn Terrace, New South Wales, Australia, 2259
      • Wyong Hospital
    • Sydney, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
    • Brisbane, Queensland, Australia, 4029
      • Royal Brisbane and Women's Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Sir Charles Gaidner Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 lead to clinically significant deterioration as per the investigator 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. They are permitted to enrol if they have clinically quiescent auto-immune conditions not requiring immunomodulation beyond low dose steroids (ie <10mg per day of prednisolone or equivalent) or topical therapies (including mesalazine or steroid enemas).
• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; Avelumab plus External Beam Radiation Therapy (EBRT)	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 Names: Radiotherapy
Experimental: Arm B; Avelumab plus Lutetium-177 (177Lu)-DOTATATE This treatment arm is now closed to recruitment	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: Lutetium-177 (177Lu)-DOTATATE; Patients allocated to Arm B will receive 177-Lu-DOTATATE treatment on 2 occasions, 8-10 weeks apart. This treatment arm is now closed to recruitment.; Other Names: Lutathera; Peptide Receptor Radionuclide Therapy (PRRT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) at 12 months	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.	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) at 24 months	Time to disease progression including rate at specific landmark timepoint of 24 months.	4 years
Overall Survival (OS) at 12 and 24 months	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.	4 years
Best Objective Response Rate (ORR) according to RECIST v1.1	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.	4 years
The safety and tolerability of 177Lu-DOTATATE or EBRT in combination with avelumab.	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.	4 years
Rate of treatment discontinuation due to toxicity	This is defined as the proportion of patients who discontinue with treatment due to treatment-related toxicity.	4 years

Collaborators and Investigators

• Sponsor: Melanoma and Skin Cancer Trials Limited
• Investigators: Study Chair: Prof Shahneen Sandhu, MBBS, FRACP, Peter MacCallum Cancer Centre, Australia

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2020
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: February 6, 2020
• First Submitted That Met QC Criteria: February 6, 2020
• First Posted (Actual): February 10, 2020

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: carcinoma; immunotherapy; radiotherapy; rare cancer; peptide receptor radionuclide therapy; neuroendocrine tumour; merkel cell; merkel cell carcinoma
• Additional Relevant MeSH Terms: Neoplasms; Infections; Virus Diseases; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; DNA Virus Infections; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Tumor Virus Infections; Polyomavirus Infections; Carcinoma, Neuroendocrine; Carcinoma; Neuroendocrine Tumors; Carcinoma, Merkel Cell; Therapeutics; Radiotherapy; lutetium Lu 177 dotatate; avelumab; Lutetium-177
• Other Study ID Numbers: 10.17

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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