IT-hu14.18-IL2 With Radiation, Nivolumab and Ipilimumab for Melanoma

NCT03958383 | Active Not Recruiting Phase 1 DMC FDA Drug

• 6 other identifiers: UW161342017-1464R35CA197078A534260SMPH\MEDICINE\HEM-ONCProtocol Version 7/30/2020
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I/II trial is designed to determine the maximum tolerated dose or the maximum administered dose of intratumoral administration of hu14.18-IL2 and to evaluate side effects of intratumoral hu14.18-IL2 when given alone, after radiation therapy, after radiation therapy and in combination with nivolumab, and after radiation therapy and in combination with nivolumab and ipilimumab in patients with melanoma that is advanced (stage IV) or with melanoma that cannot be removed by surgery and is considered surgically incurable. Hu14.18-IL2 is a molecule called a fusion protein that can bind to some tumor cells and cause immune cells to become activated to kill tumor cells. Radiation therapy is a type of cancer treatment that uses beams of high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with immune checkpoint inhibitors, such as nivolumab and ipilimumab, can help the body's immune system attack cancer by releasing the "brakes" on the immune system to allow cancer fighting immune cells to remain activated. This study will evaluate whether giving intratumoral hu14.18-IL2 with radiation therapy, nivolumab and ipilimumab has antitumor activity for participants with advanced melanoma. After completion of study treatment, participants are followed up at 30 days, every 12 weeks for up to 2 years, and then every 6 months thereafter.

Conditions

Melanoma

Outcome Measures

Primary Outcomes (3)

• Incidence of Adverse Events

  The number and severity of toxicity incidents per (Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 will be summarized with frequency and proportion. The 95% confidence interval for the proportion of subjects with severe complications (grade 3 or higher toxicities) will be constructed.

  up to 2 years

• Maximum Tolerated Dose (MTD)

  The MTD is defined as the highest dose level at which less than 33% of the subjects experience a Dose Limiting Toxicity (DLT). DLT will be defined as grade 3 or 4 toxicity that is possibly, probably or definitely related to IT-hu14.18-IL2 graded according to CTCAE v. 5.0. A standard 3+3 design and descriptive statistics will primarily be generated to summarize the data.

  up to 21 days

• Maximum Administered Dose (MAD)

  The MAD is defined as the highest safely tolerated dose where less than 33% subjects experience a DLT but no higher dose level has been assessed. Descriptive statistics will primarily be generated to summarize the data.

  up to 21 days

Secondary Outcomes (19)

• Objective Tumor Response (OR)

  Up to 5 years

• Progression Free Survival (PFS)

  Up to 5 years

• Overall Survival (OS)

  Up to 5 years

• Clinical Benefit (CB)

  Up to 5 years

• Duration of Response

  Up to 5 years

Other Outcomes (11)

• Analysis of Antibody Resistance: OR

  Up to 5 years

• Analysis of Antibody Resistance: Duration of Response

  Up to 5 years

• Analysis of Antibody Resistance: CB

  Up to 5 years

Study Arms (1)

Experimental Groups

EXPERIMENTAL

PHASE IA: As described above. Participants receive hu14.18-IL2 fusion protein intratumorally (IT). PHASE IB: As described above. Participants undergo palliative RT and hu14.18-IL2 fusion protein IT as in phase IA. PHASE IC: As described above. Participants undergo palliative RT, receive nivolumab, and hu14.18-IL2 fusion protein IT as in phase IA. PHASE ID: As described above. Participants undergo palliative RT, receive nivolumab in combination with ipilimumab, and hu14.18-IL2 fusion protein IT as in phase IA.

Biological: hu14.18-IL2; Radiation: Radiation Therapy; Biological: Nivolumab; Biological: Ipilimumab

Interventions

hu14.18-IL2 BIOLOGICAL

A recombinant fusion protein linking the monoclonal antibody (mAb) hu14.18 with interleukin-2 (IL2), administered IT

Also known as: immunocytokine

Experimental Groups

Radiation Therapy RADIATION

Palliative radiation therapy

Also known as: Radiotherapy

Experimental Groups

Nivolumab BIOLOGICAL

Human programmed death receptor (PD-1) blocking antibody, given IV

Also known as: anti-PD-1

Experimental Groups

Ipilimumab BIOLOGICAL

Monoclinal antibody that targets cytoxic T-lymphocyte-associated protein 4 (CTLA-4), given IV

Also known as: anti-CTLA-4

Experimental Groups

Eligibility Criteria

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

You may qualify if:

• Subjects must have histologically proven, malignant melanoma, that is advanced (stage IV) or is unresectable and therefore considered surgically incurable
• Subject's disease must be measurable by immune-related RECIST criteria using clinical assessments or imaging
• Subjects must have at least one (1), but preferably two (2), sites of readily accessible, superficial disease (i.e., cutaneous, subcutaneous, and/or readily-palpable lymphadenopathy) that are amenable to repeated hu14.18-IL2 injections and two (2) to four (4) biopsies (designated Lesions A (index lesion) and B). These lesions must be at least 1 cm, but no greater than 5 cm, in longest diameter.
• If there are two lesions, one will be injected with hu14.18-IL2 and undergo biopsies. The second will not undergo injections with hu14.18-IL2, but will undergo two biopsies and be observed clinically. It is preferable, but not required, that these lesions have not received prior RT.
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Subjects must have received or declined at least one FDA approved immunotherapy treatment demonstrating an impact on survival (i.e: anti-CTLA-4 antibody, anti-PD-1 antibody, IL2, etc).
• Subjects with Central Nervous System (CNS) metastases are eligible if the CNS lesions are stable for at least 2 months and if tapered off treatment doses of systemic corticosteroids for at least 2 weeks prior to enrollment on the trial. Management with maintenance physiologic doses of corticosteroids is acceptable.
• Subjects to be entered into Phase IB, IC and ID must be evaluated by a radiation oncologist and determined to have a need for palliative RT based on current or imminent symptoms at a tumor site that is also injectable. If palliative RT is needed to one or more disease sites, a separate site of disease that does not require RT must remain to enable assessment of systemic disease response.
• Subjects must have adequate bone marrow, liver, and renal function as defined by:
• Total White Blood Cell (WBC) \> 3,000/mm3 (or total neutrophil count \> 1,500/mm3), platelets \>100,000/mm3, and hemoglobin \> 10 g/dL.
• AST/ALT ≤ 3 x the upper limit of normal. Total bilirubin ≤ 1.5 x the upper limit of normal (\< 3.0 mg/dL for subjects with Gilbert's Syndrome).
• Serum creatinine ≤ 1.5 x the upper limit of normal
• Subjects with a history of ischemic cardiac disease must complete a stress radionuclide scan with results that show no evidence of myocardial ischemia or heart failure, as well as normal pulmonary function
• Subjects must be willing and able to provide informed written consent for the study.
• Subjects must have no immediate requirements for palliative chemotherapy, or surgery. Subjects in Arm 1A must have no immediate requirement for palliative RT.

You may not qualify if:

• Subjects with a diagnosed auto-immune disease (exceptions: subjects with controlled diabetes mellitus type I, thyroid disease, vitiligo and alopecia areata not requiring treatment with immunosuppressants are eligible)
• Subjects with a history of diabetes mellitus requiring systemic therapy within the past 3 months (i.e. either oral hypoglycemic agents or insulin) must have a documented Hemoglobin A1c \<8.0% at the time of enrollment.
• Subjects with known genetic conditions causing pre-disposition to RT toxicity (i.e: Li-Fraumeni, ATM deficiency, active scleroderma, etc).
• Subjects who cannot provide independent, legal, informed consent.
• Women of childbearing potential will be excluded if they are pregnant, nursing, or not willing to use effective contraception, as discussed with the treating physician, during the treatment period. A negative pregnancy test (serum or urine) is required for women of child bearing potential within 14 days before study registration.
• A person of childbearing potential is anyone (regardless of sexual orientation, gender identity, having undergone tubal ligation, or remaining celibate by choice) who was born with a uterus and at least one ovary and meets the following criteria
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had a menses at any time in the preceding 12 consecutive months).
• Subjects with symptoms of ischemic cardiac disease, congestive heart failure, or myocardial infarction within the immediate preceding 6 months and/or uncontrolled cardiac rhythm disturbance
• Subjects with significant psychiatric disabilities or seizure disorders
• Subjects with symptomatic pleural effusions or ascites.
• Subjects with organ allografts
• Subjects who require, or are likely to require, systemic treatment doses of corticosteroids, or other immunosuppressive drugs, or have used them within 2 weeks of registration (clarification: subjects receiving physiologic maintenance or replacement doses of systemic steroids are eligible).
• Subjects with significant intercurrent illnesses per physician discretion.
• Subjects with active or acute infections or active peptic ulcers, unless these conditions are adequately corrected or controlled, in the opinion of the treating physician.

Sponsors & Collaborators

• University of Wisconsin, Madison: lead
• National Cancer Institute (NCI): collaborator
• Bristol-Myers Squibb: collaborator
• AnYxis Immuno-Oncology GmbH: collaborator
• Provenance Biopharmaceuticals: collaborator

Study Sites (1)

University of Wisconsin Carbone Cancer Center

Madison, Wisconsin, 53792, United States

Location

Related Links

• University of Wisconsin Carbone Cancer Center

MeSH Terms

Conditions

Melanoma

Interventions

lorukafusp alfa; Radiotherapy; Nivolumab; spartalizumab; Ipilimumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Paul Sondel, MD, PhD

  University of Wisconsin, Madison

  PRINCIPAL INVESTIGATOR

• Mark R Albertini, MD

  University of Wisconsin, Madison

  STUDY CHAIR

Study Design

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

Model Details: 3+3 dose escalation design to determine maximum tolerated dose / maximum administered dose for each of 4 cohorts

Study Record Dates

• First Submitted: May 7, 2019
• First Posted: May 22, 2019
• Study Start: January 30, 2020
• Primary Completion: January 6, 2024
• Study Completion (Estimated): August 15, 2026
• Last Updated: April 18, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)