Tebentafusp-tebn With LDT in Metastatic UM

Thomas Jefferson University

Status and phase: Not yet enrolling; Phase 2; Phase 1

Conditions: Metastatic Uveal Melanoma

Treatments: Drug: GM-CSF (Sargramostim); Drug: Tebentafusp-Tebn; Drug: BCNU

Study type: Interventional

Funder types: Other

Identifiers

NCT06626516

2024-3117

31444 (Other Identifier)

Details and patient eligibility

About

We will conduct a multicenter, open label phase I/ II trial to assess the safety and clinical efficacy of tebentafusp-tebn in combination with liver-directed therapies in HLA-A*0201 positive patients with metastatic uveal melanoma. In Part 1 of the study, we will investigate the safety and efficacy of tebentafusp-tebn in combination with hepatic IE in patients with a low to moderate hepatic disease burden. In Part 2, we will investigate the efficacy of tebentafusp-tebn in combination with TACE in patients with bulky hepatic disease.

Enrollment: 109 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Age ≥18 years of age 2. Histologically or cytologically confirmed metastatic uveal melanoma in the liver. Patients must have at least one measurable liver metastasis that is ≥ 10 mm in longest diameter by CT scan or MRI. Extra-hepatic disease is allowed.

2. Tumor Size Criteria: i. Part 1: Total volume of tumor must be < 50% of the liver involvement by CT or MRI; M1a or M1b disease with largest tumor ≤ 5 cm ii. Part 2: M1b disease with largest tumor > 5 cm, M1c disease, or ≥ 50% liver involvement by CT or MRI 4. No prior systemic treatment with tebentafusp-tebn 5. Prior therapy: i. Part 1: Patients must be treatment naïve in the metastatic setting.

3. Prior surgery or ablation for oligometastatic disease is allowable.

4. Palliative radiation of non-target lesions also allowable. ii. Part 2: Patients may have had prior systemic therapy with chemotherapy, immunotherapy, or targeted therapy. They can also have had prior liver directed therapy including surgery, ablation, immunoembolization, or radioembolization. However cannot have had more than two prior lines of treatment total.

5. HLA-A*0201 positive 7. ECOG performance status or 0 or 1 at the time of screening 8. Life expectancy of greater than 3 months as assessed by the investigator 9. Patients must have normal organ and bone marrow function as defined below:

6. Platelet count ≥ 100,000/mm³

7. Hemoglobin > 8.0g/dL

8. AST and/or ALT < 3x upper limited of normal (ULN)

9. Total bilirubin ≤ 2.0 mg/ml

10. Note: Patients with hyperbilirubinemia clinically consistent with an inherited disorder of bilirubin metabolism (e.g., Gilbert syndrome) will be eligible at the discretion of the treating physician and/or the principal investigator.

11. PT/PTT < 1.5x ULN

12. Serum creatinine ≤ 2.0 mg/dl or a creatinine clearance > 60mL/min

13. Potassium, magnesium, corrected calcium, and phosphate within normal laboratory parameters 10. Women must not be pregnant or breast-feeding. 11. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for the 6 months after the final dose of the study drug. Women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to study entry. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.

    12. Male patients treated or enrolled on this protocol must be surgically sterile or use double barrier contraception methods from enrollment through treatment, and for 6 months after completion of study therapy.

    13. Ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

Parts 1 and 2:

1. Failure to meet any of the criteria set forth in the Inclusion criteria section
2. History of prior tebentafusp-tebn use
3. Prior chemoembolization in Part 2 is not permitted
4. History of severe immediate or delayed hypersensitivity reaction to biologic drugs, monoclonal antibodies, iodinated contrast agent
5. Presence of symptomatic liver failure including ascites and hepatic encephalopathy
6. Presence of symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require corticosteroids within 21 days prior to initiation of study therapy. Patients with brain metastases may be eligible if lesions have been treated with local therapy and there is no evidence of CNS disease progression for at least 4 weeks as measured by MRI prior to first dose of study drug
7. History of another malignancy except for: 1) those who have been disease-free for 3 years prior to study treatment; 2) patients with a history of completely resected non-melanoma skin cancer; 3) patients with indolent secondary malignancies not requiring active therapy; 4) patients with completely resected carcinoma in situ. Consult the study Principal Investigator if unsure whether second malignancies meet the requirements specified above.
8. Major surgery within 2 weeks of the first dose of study drug (minimally invasive procedures such as bronchoscopy, tumor biopsy, insertion of a central venous access device, and insertion of a feeding tube are not considered major surgery and are not exclusionary)
9. Radiotherapy within 2 weeks of the first dose of study drug, with the exception of palliative radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful tumor mass
10. No outstanding toxicities from prior therapies greater than Grade 1. Except for prior immune related side effects such as endocrinopathy that are managed with a stable dose of thyroid or steroid supplement.
11. Use of any investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study therapy and during the study.
12. Use of hematopoietic colony-stimulating growth factors (eg. G-CSF, GMCSF, M-CSF) within 14 days prior to study treatment initiation. An erythroid-stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is not red blood cell transfusion dependent.
13. Known history of human immunodeficiency virus infection (HIV). Testing for HIV is not necessary unless clinically indicated
14. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Testing for HBV or HCV status is not necessary unless clinically indicated or if the patient has a history of HBV or HCV infection.
15. Patients receiving systemic steroid therapy or any immunosuppressive medication. Local steroid therapies (eg, otic, ophthalmic, intra-articular or inhaled medications) are acceptable.
16. History of bleeding diathesis
17. Pregnant, likely to become pregnant, or breastfeeding women
18. Uncontrolled concurrent illness, evaluated at investigator discretion
19. Biliary obstruction, biliary stent or prior biliary surgery except cholecystectomy, or any anatomic abnormalities that would interfere with immunoembolization or chemoembolization
20. Patients with occlusion of the main portal vein
21. Inadequate collateral flow around an occluded portal vein as determined by angiography
22. Arteriovenous shunt identified on arteriography of the hepatic artery
23. Any medical condition that, in the Investigator's judgement, would prevent patient participation in the clinical study due to safety concerns, compliance with study procedures or interpretation of study results

Part 1 Only:

a. History of severe immediate or delayed hypersensitivity reaction to GM-CSF

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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109 participants in 4 patient groups

Part 1A: Safety Lead-in

Experimental group

Description:

Phase I safety lead-in followed by a phase II trial with 6-month PFS rate as the preliminary efficacy endpoint. We will conduct a single-arm of 18 patients treated with combination therapy (tebentafusp-tebn with hepatic IE with GM-CSF), with the first cohort of six patients being enrolled in a safety lead in. All patients will receive a 4-week induction course of tebentafusp-tebn alone (Cycle 1) using the approved step-up dosing regimen. Should the 4th dose be tolerated well as an outpatient, patients will receive their first IE treatment on Cycle 2 week 1 followed by continued weekly tebentafusp-tebn on weeks 2, 3, and 4 of Cycle 2. Should Cycle 2 be well tolerated, patients may receive both tebentafusp-tebn and IE on Week 1 of subsequent cycles, with tebentafusp administered alone on weeks 2-4 of subsequent cycles.

Treatment:

Drug: Tebentafusp-Tebn

Drug: GM-CSF (Sargramostim)

Part 1B: Combination

Active Comparator group

Description:

If the safety and preliminary efficacy in Part 1A are met, we will then proceed with a randomized phase II trial. 52 patients will be randomized in a 2:1 ratio to receive tebentafusp-tebn in combination with hepatic IE or tebentafusp-tebn alone, with PFS as the primary endpoint. Patients randomized to tebentafusp-tebn + IE arm will be treated as Part 1A.

Treatment:

Drug: Tebentafusp-Tebn

Drug: GM-CSF (Sargramostim)

Part 1B: Tebentafusp-tebn alone

Active Comparator group

Description:

If the safety and preliminary efficacy in Part 1A are met, we will then proceed with a randomized phase II trial. 52 patients will be randomized in a 2:1 ratio to receive tebentafusp-tebn in combination with hepatic IE or tebentafusp-tebn alone, with PFS as the primary endpoint. Patients randomized to tebentafusp-tebn alone will receive weekly treatment using the approved step-up dosing regimen.

Treatment:

Drug: Tebentafusp-Tebn

Part 2: Efficacy of Combo

Active Comparator group

Description:

To assess the efficacy of tebentafusp-tebn in sequence with TACE in HLA-A\*0201-positive patients with metastatic uveal melanoma to the liver

Treatment:

Drug: BCNU

Drug: Tebentafusp-Tebn