TebeMRD

A Phase II Non-Randomized, Open-label, Multi-centre Study of the Safety and Efficacy of Tebentafusp in Melanoma with Molecular Relapsed Disease

Chief Investigator: Prof. Mark Middleton

Sponsor: University of Oxford

EudraCT number: 2019-003946-34

TebeMRD is being funded by Immunocore, through an unrestricted educational grant.

This is an unblinded non-randomised, open labelled, safety and efficacy study involving 2 patient cohorts:

• A: Cutaneous melanoma with molecular relapsed disease (MRD)
• B: Uveal melanoma with MRD

Approximately 850 patients (600 cutaneous melanoma, 250 uveal melanoma) will be enrolled from 50 centres to screen for HLA-A*0201 status and then followed for up to 12 months for MRD at those same centres. Patients identified with MRD will be invited to be treated with tebentafusp at up to 10 treating centres in the UK.  Patients will receive up to six months of tebentafusp, administered weekly IV, and then followed-up for one year for molecular and clinical relapse.

This study will be conducted in patients with cutaneous or uveal melanoma at high risk of recurrence. Given the mechanism of action of tebentafusp, the study is limited to patients with the HLA-A*0201 subtype.

The patient population will be drawn from those completing adjuvant or local therapy for intermediate or high risk melanoma. Potential participants will be approached as they enter the last 3 months of adjuvant treatment for resected cutaneous melanoma, or within 9 months of completing such treatment. In the case of uveal melanoma, patients will be approached within 3 years of completing treatment for their primary tumour or oligometastatic disease.

Open to recruitment

ACTIVE SITES

Churchill Hospital, Oxford

Mount Vernon Cancer Centre, Rickmansworth

Clatterbridge Cancer Centre, Liverpool

University College London Hospital

The Christie Hospital, Manchester

A patient will be eligible for inclusion in this study if all of the following criteria apply:

1. Uveal or cutaneous melanoma with MRD detected in molecular screening.
2. Written (signed and dated) informed consent and be capable of co-operating with protocol
3. Male or female, Age ³ 18 years.
4. Life expectancy of at least 3 months.
5. ECOG performance score of 0 or 1.
6. No evidence of metastatic disease on a CT scan of neck/thorax/abdomen/pelvis for cohorts A and B and also on MRI liver for uveal melanoma for cohort B.
7. Those receiving prior immunotherapy must have recovered from any immune-mediated adverse events (≤ grade 1) other than endocrinopathies on stable replacement therapy.
8. Haematological and biochemical indices within the ranges shown in the trial protocol.

A patient will not be eligible for the trial if any of the following apply:

1. Treatment with any other investigational agent, or participation in another interventional clinical trial within 28 days prior to enrolment.
2. Uveal or cutaneous melanoma patients who present radiologically or clinically detectable disease during screening.
3. Active infection requiring systemic antibiotic therapy. Patients requiring systemic antibiotics for infection must have completed therapy before Screening is initiated.
4. Other psychological, social or medical condition, physical examination finding or a laboratory abnormality that the Investigator considers would make the patient a poor trial candidate or could interfere with protocol compliance or the interpretation of trial results.
5. Any other active malignancy, with the exception of malignancies that were treated curatively and have not recurred within 2 years after completion of treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
6. Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV. This study does not require testing to confirm eligibility unless clinically indicated.
7. Clinically significant cardiac disease or impaired cardiac function (New York Heart Association grade ≥ 2), including myocardial infarction or unstable angina pectoris within 6 months of screening.
8. Active autoimmune disease or a documented history of autoimmune disease within 3 years of screening (diabetes mellitus, vitiligo, managed hypothyroidism, psoriasis and managed asthma are not exclusions).
9. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For cytotoxic agents that have major delayed toxicity and any prior immunotherapy approach, 4 weeks is indicated as washout period
10. Presence of NCI CTCAE ≥ grade 2 toxicity (except alopecia, peripheral neuropathy, and ototoxicity, which are excluded if ≥ NCI CTCAE grade 3) due to prior cancer therapy.
11. Patients currently requiring chronic, systemic corticosteroid therapy at any dose for longer than 2 weeks. Replacement treatment for pituitary or adrenal insufficiency is permitted.  Local steroid therapies (e.g. otic, ophthalmic, intra-articular, or inhaled medications) are acceptable.
12. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.  Non-live vaccination (e.g. influenza) are permitted anytime during treatment.
13. Major surgery as defined by the investigator within 2 weeks of the first dose of study treatment (minimally invasive procedures such as bronchoscopy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery).
14. Pregnant or lactating women, or women of childbearing potential unless effective methods of contraception are used.
15. Women of child-bearing potential who are sexually active with a non-sterilized male partner, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective contraception during study treatment, and must agree to continue using such precautions for 6 months after the final dose of investigational product; cessation of birth control after this point should be discussed with a responsible physician.
16. Male patients must be surgically sterile or use double barrier contraception method from enrolment through treatment and for 6 months following administration of the last dose of study drug.

• Estimate the rate of molecular response (MR) to tebentafusp in each of the 2 cohorts:
• Cutaneous melanoma with MRD
• Uveal melanoma with MRD

• Evaluate the efficacy of Tebentafusp in each cohort
• Assess the safety and tolerability of tebentafusp in MRD
• Assess the rate of molecular relapse in both cohorts
• Characterise pharmacodynamic changes with tebentafusp treatment
• Preliminary evaluation of response rate in gp100 expressing melanoma