TerminatedNCT03958383Updated Jun 3, 2026Results posted

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

A Phase 1/2 interventional study of hu14.18-IL2 and Radiation Therapy in Melanoma, sponsored by University of Wisconsin, Madison. Terminated at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-06-03.

Sponsored by University of Wisconsin, Madison · Phase 1/2, Interventional, and Treatment

Why this study was terminated

Administrative

Phase: Phase 1/2
Study type: Interventional
Enrollment: 8
Allocation: Not applicable
Ages: 18 Years and older
Sex: All

Study 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.

Read the detailed description

PRIMARY OBJECTIVES:

I. Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of intratumoral (IT)-Hu14.18-IL2 fusion protein (hu14.18-IL2) in subjects with advanced melanoma (Phase IA)

II. Evaluate the safety and tolerability of IT-hu14.18-IL2 when given alone (Phase IA)

III. Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of IT-hu14.18-IL2 after receiving palliative radiation therapy (RT) in subjects with advanced melanoma (Phase IB)

IV. Evaluate the safety and tolerability of the combination of palliative RT with IT-hu14.18-IL2 (Phase IB)

V. Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of IT-hu14.18-IL2 after receiving palliative RT and in combination with nivolumab in subjects with advanced melanoma (Phase IC)

VI. Evaluate the safety and tolerability of the combination of palliative RT, nivolumab and IT-hu14.18-IL2 (Phase IC)

VII. Determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of IT-hu14.18-IL2 after receiving palliative RT and in combination with nivolumab and ipilimumab in subjects with advanced melanoma (Phase ID)

VIII. Evaluate the safety and tolerability of the combination of palliative RT, nivolumab, ipilimumab and IT-hu14.18-IL2 (Phase ID)

IX. Evaluate local and systemic objective tumor responses to treatment with IT-hu14.18-IL2 in combination with palliative RT, nivolumab, and ipilimumab (Phase ID)

SECONDARY OBJECTIVES:

I. Evaluate progression-free survival (PFS), overall survival (OS), clinical benefit (CB, defined as complete response (CR) + partial response (PR) + stable disease (SD)) and duration of response to hu14.18-IL2 in combination with RT, nivolumab and ipilimumab.

II. Evaluate pathologic (tissue) evidence of immune response at the injection site and untreated sites.

III. Evaluate PFS, CB and duration of response to hu14.18-IL2 in combination with palliative RT, nivolumab and ipilimumab based on resistance to prior treatment with anti-CTLA-4 and/or anti PD1/PD-L1 antibody.

IV. Evaluate serial serum samples to determine the pharmacokinetics of hu14.18-IL2 administered intratumorally.

V. Evaluate each subject's tumor cells for expression of GD2 and PD-L1, and determine if either antitumor activity or selected treatment-associated biologic effects are more likely for tumors that are GD2+ then GD2- and PD-L1+ than PD-L1-.

VI. Evaluate whether PD-L1 expression is induced or augmented from baseline following initiation of treatment (by comparing serial biopsies).

VII. Evaluate the immunologic activation induced in vivo by IT-hu14.18-IL2, addressed by in vitro cellular, serologic and flow cytometry immune assays.

VIII. Evaluate for histological evidence of antitumor activity based on the presence of necrotic tumor cells, inflammatory infiltrate, cellular phenotype of infiltrate, and presence of hu14.18-IL2 within the tumor at selected post-treatment timepoints.

IX. Evaluate circulating tumor cells, exosomes, endogenous antibodies, and/or deoxyribonucleic acid (DNA) as exploratory biomarkers associated with clinical response to IT-hu14.18-IL2 in combination with RT, nivolumab and ipilimumab.

X. Evaluate serial peripheral blood mononuclear cell (PBMC) samples to monitor the induction of T cell responses to melanoma-associated antigens.

XI. Evaluate objective tumor responses, both locally and systemically (by immune-related response criteria), in Phases IA, IB and IC of this trial (involving IT-hu14.18-IL2 alone and in combinations with palliative RT, and with palliative RT and nivolumab, respectively).

OUTLINE: This is a dose escalation study of hu14.18-IL2 fusion protein.

PHASE IA: Participants receive hu14.18-IL2 fusion protein intratumorally (IT) once daily (QD) on days 1-3. Treatment repeats every 21 days for cycles 1-4. Participants who are eligible may continue to receive hu14.18-IL2 fusion protein maintenance therapy QD on days 1-3 beginning with cycle 5. Maintenance cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. A total of 9-18 participants will be enrolled in 3 escalating dose levels to determine the Maximum Tolerated Dose (MTD)/Maximum Administered Dose (MAD) of hu14.18-IL2 in Phase IA.

PHASE IB: Participants undergo palliative RT on days -8 to -4 of cycle 1 only. Participants also receive hu14.18-IL2 fusion protein IT as in phase IA. Treatment with hu14.18-IL2 repeats every 21 days for cycles 1-4. Participants who are eligible may continue to receive hu14.18-IL2 fusion protein maintenance therapy QD on days 1-3 beginning with cycle 5. Maintenance cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. The MTD/MAD of IT-hu14.18-IL2 following palliative RT will be determined starting 1 dose level below the Phase IA determined MTD/MAD of IT-hu14.18-IL2 up to the Phase IA determined MTD/MAD.

PHASE IC: Participants undergo palliative RT on days -8 to -4 of cycle 1 only. Nivolumab (3 mg/kg) is given every 2 weeks for up to 1 year with the initial dose given between day -7 and day -1 of cycle 1. Participants also receive hu14.18-IL2 fusion protein IT as in phase IA. Treatment with hu14.18-IL2 repeats every 21 days for cycles 1-4. Participants who are eligible may continue to receive hu14.18-IL2 fusion protein maintenance therapy QD on days 1-3 beginning with cycle 5. Maintenance cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. The MTD/MAD of IT-hu14.18-IL2 following palliative RT in combination with nivolumab will be determined starting 1 dose level below the Phase IB determined MTD/MAD of IT-hu14.18-IL2 up to the Phase IB determined MTD/MAD.

PHASE ID: Participants undergo palliative RT on days -8 to -4 of cycle 1 only. Nivolumab (1 mg/kg) in combination with ipilimumab (3 mg/kg) is given every 3 weeks for 4 cycles with the initial dose given between day -7 and day -1 of cycle 1. Following 4 cycles, no additional ipilimumab will be administered. Following cycle 4, maintenance nivolumab (3 mg/kg) can be given for up to one year. Participants also receive hu14.18-IL2 fusion protein IT as in phase IA. Treatment with hu14.18-IL2 repeats every 21 days for cycles 1-4. Participants who are eligible may continue to receive hu14.18-IL2 fusion protein maintenance therapy QD on days 1-3 beginning with cycle 5. Maintenance cycles repeat every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity. The MTD/MAD of IT-hu14.18-IL2 following palliative RT in combination with nivolumab and ipilimumab will be determined starting 1 dose level below the Phase IC determined MTD/MAD of IT-hu14.18-IL2 up to the Phase IC determined MTD/MAD. A total of 28 participants will be enrolled at the Phase ID MTD/MAD of IT-hu14.18-IL2.

Conditions studied

Melanoma

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Melanoma 3,006

In context

Melanoma

3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.

This study's enrollment of 8 is below the median of 38 across 2,351 interventional studies indexed under Melanoma.

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Lead sponsor

University of Wisconsin, Madison is the lead sponsor of 1,161 studies on the registry; 182 are open to participants now.

Of its 151 completed or terminated interventional studies of FDA-regulated products, 114 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

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.
Subjects must be willing and able to discontinue antihypertensive medications if advised to do so for the days of hu14.18-IL2 administration.
Subjects must have a washout period of at least 28 days between any prior systemic anti-cancer therapy (including immunotherapies) and the first dose of study drug(s).

Exclusion criteria

Exclusion Criteria:

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.
Subjects with a second malignancy other than adequately treated non-melanoma skin cancer. Subjects will be considered eligible if they have been continuously disease free for > 5 years from a second malignancy prior to the time of enrollment.
Subjects with known human immunodeficiency virus (HIV) infection, active or chronic hepatitis B or hepatitis C infection, or with clinical evidence of hepatitis.
Subjects with a clinically significant neurologic deficit or objective peripheral neuropathy (Grade ≥2).
Subjects with known hypersensitivity to hu14.18-IL2 or human immunoglobulin, or those who experienced significant immune-related adverse events requiring treatment with steroids or other immunosuppressant therapy during prior treatment with ipilimumab, or anti-PD1/PD-L1 checkpoint blockade therapy.

Study design

Phase: Phase 1 / Phase 2
Primary purpose: Treatment
Allocation: Not applicable
Intervention model: Single group
Masking: None (open label)
Enrollment: 8 participants (actual)

Study arms

Experimental
Experimental Groups
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

Biologicalhu14.18-IL2
A recombinant fusion protein linking the monoclonal antibody (mAb) hu14.18 with interleukin-2 (IL2), administered IT
Also known as: immunocytokine
RadiationRadiation Therapy
Palliative radiation therapy
Also known as: Radiotherapy
BiologicalNivolumab
Human programmed death receptor (PD-1) blocking antibody, given IV
Also known as: anti-PD-1
BiologicalIpilimumab
Monoclinal antibody that targets cytoxic T-lymphocyte-associated protein 4 (CTLA-4), given IV
Also known as: anti-CTLA-4

What researchers measure

Primary outcomes

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.
Time frame: 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.
Time frame: 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.
Time frame: up to 21 days

Secondary outcomes

Objective Tumor Response (OR)
OR will be summarized using descriptive statistics. Furthermore, a point estimate along with the 95% confidence interval for the proportion of subjects with OR will be provided. Clinical outcome of OR will be summarized by dose level for Phase IC.
Time frame: Up to 5 years
Progression Free Survival (PFS)
The length of time from the start of treatment until disease progression or death. Kaplan-Meier method will be used to estimate the survival distribution of progression-free survival for the Phase ID expansion cohort.
Time frame: Up to 5 years
Overall Survival (OS)
The length of time from the start of treatment until death from any cause. Kaplan-Meier method will be used to estimate the survival distribution of overall survival for the Phase ID expansion cohort.
Time frame: Up to 5 years
Clinical Benefit (CB)
The status of achieving complete response, partial response or stable disease in response to treatment.
Time frame: Planned to be collected for up to 5 years, study closed early and this data was collected for approximately 8 months
Duration of Response
The length of time from documentation of tumor response until disease progression. Kaplan-Meier method will be used to estimate the survival distribution for the Phase ID expansion cohort.
Time frame: Up to 5 years
Immunologic Parameters: Change in Antibody Dependent Cell-Mediated Toxicity (ADCC) Function
Immunologic activation induced in vivo by intratumoral (IT)-hu14.18-IL2 fusion protein will be evaluated using both in vivo and in vitro analyses. Changes between assessment time points will be evaluated using a paired t-test or non-parametric Wilcoxon signed rank test, depending on the scale and distribution of the endpoint.
Time frame: Baseline, Cycle 3 day 1, Cycle 5 day 1, End of Treatment (up to 13 cycles) (cycles 1-4 are 21 days, 5+ are 28 days)
Immunologic Parameters: Change in Natural Killer (NK) Cell Function
Immunologic activation induced in vivo by intratumoral (IT)-hu14.18-IL2 fusion protein will be evaluated using both in vivo and in vitro analyses. Changes between assessment time points will be evaluated using a paired t-test or non-parametric Wilcoxon signed rank test, depending on the scale and distribution of the endpoint.
Time frame: Baseline, Cycle 3 day 1, Cycle 5 day 1, End of Treatment (up to 13 cycles) (cycles 1-4 are 21 days, 5+ are 28 days)
Immunologic Parameters: Change in Soluble Interleukin-2 Receptor Alpha (IL-2 Alpha) Levels
Immunologic activation induced in vivo by intratumoral (IT)-hu14.18-IL2 fusion protein will be evaluated using both in vivo and in vitro analyses. Changes between assessment time points will be evaluated using a paired t-test or non-parametric Wilcoxon signed rank test, depending on the scale and distribution of the endpoint.
Time frame: Baseline; Cycle 1 days 1,4,8; Cycle 4 days 1,4,8; Cycle 7 days 1,4,8; Cycle 10 day 1,4,8 (cycles 1-4 are 21 days, 5+ are 28 days)
Histological Parameters: Change in Necrotic Tumor Cells From Baseline
For the primary parameters to be assessed on the resected melanoma an objective scoring system will be established by a pathologist, grading each specimen with a score of 0, +, ++, +++. Changes in number of Necrotic Tumor Cells from baseline will be evaluated using a paired McNemar's test for binary outcomes. Quantitative assessment of necrosis of tumor cells will be measured and scored with a value ranging from 0% - 100% of tumor area.
Time frame: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycles 1-4 are 21 days)
Histological Parameters: Change in Apoptosis From Baseline
For the primary parameters to be assessed on the resected melanoma an objective scoring system will be established by a pathologist, grading each specimen with a score of 0, +, ++, +++.
Time frame: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days)
Histological Parameters: Change in Inflammatory Infiltrate in the Tumor From Baseline
For the primary parameters to be assessed on the resected melanoma an objective scoring system will be established by a pathologist, grading each specimen with a score of 0, +, ++, +++.
Time frame: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days)
Histological Parameters: Change in Cellular Phenotype of Infiltrate
Cellular phenotype of infiltrate within the tumor will be summarized by descriptive statistics. Changes from baseline will be evaluated using a paired McNemar's test for binary outcomes.
Time frame: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days)
Histological Parameters: Change in hu14.18-IL2 in the Tumor From Baseline
Presence hu14.18-IL2 within the tumor will be summarized by descriptive statistics. Changes from baseline will be evaluated using a paired McNemar's test for binary outcomes.
Time frame: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days)
Pharmacokinetic (PK) Parameters: Alpha Half-life
Pharmacokinetic assessments will be performed on multiple serum specimens for each subject. The analysis of all PK parameters will be performed using the PK analysis population. The distribution half-life called alpha half-life (t1/2 alpha) will be summarized by dose level with simple summary statistics.
Time frame: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)
Pharmacokinetic (PK) Parameters: Beta Half-life
Pharmacokinetic assessments will be performed on multiple serum specimens for each subject. The analysis of all PK parameters will be performed using the PK analysis population. The elimination half-life called beta half-life (t1/2 beta) will be summarized by dose level with simple summary statistics.
Time frame: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)
Pharmacokinetic (PK) Parameters: Area Under the Curve (AUC)
Pharmacokinetic assessments will be performed on multiple serum specimens for each subject. The analysis of all PK parameters will be performed using the PK analysis population. AUC will be summarized by dose level with simple summary statistics.
Time frame: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)
Pharmacokinetic Parameters: Clearance (CL)
Pharmacokinetic assessments will be performed on multiple serum specimens for each subject. The analysis of all PK parameters will be performed using the PK analysis population. Clearance will be summarized by dose level with simple summary statistics.
Time frame: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)
Pharmacokinetic (PK) Parameters: Relationship Between Dose and AUC
Scatterplots will be used to explore possible associations between the dose and area under the curve (AUC). The Jonckheere-Terpstra trend test will be performed to determine the significance of the association between increasing dose level and AUC.
Time frame: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)
Pharmacokinetic (PK) Parameters: Relationship PK Parameters and Toxicity
Logistic regression analyses will be performed to correlate PK parameters with toxicity (grade \>= 3 vs. grade 0-2) and response.
Time frame: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)

Other outcomes

Analysis of Antibody Resistance: OR
Clinical outcomes such as OR, duration of response, CB, PFS, and OS will be analyzed separately among subjects who were resistant to prior treatment with anti-CTLA-4 and/or anti-PD1/PD-L1 antibodies and those who lacked resistance in a subgroup analysis. This comparison is by necessity exploratory in nature and hypothesis generating.
Time frame: Up to 5 years
Analysis of Antibody Resistance: Duration of Response
Clinical outcomes such as OR, duration of response, CB, PFS, and OS will be analyzed separately among subjects who were resistant to prior treatment with anti-CTLA-4 and/or anti-PD1/PD-L1 antibodies and those who lacked resistance in a subgroup analysis. This comparison is by necessity exploratory in nature and hypothesis generating.
Time frame: Up to 5 years
Analysis of Antibody Resistance: CB
Clinical outcomes such as OR, duration of response, CB, PFS, and OS will be analyzed separately among subjects who were resistant to prior treatment with anti-CTLA-4 and/or anti-PD1/PD-L1 antibodies and those who lacked resistance in a subgroup analysis. This comparison is by necessity exploratory in nature and hypothesis generating.
Time frame: Up to 5 years
Analysis of Antibody Resistance: PFS
Clinical outcomes such as OR, duration of response, CB, PFS, and OS will be analyzed separately among subjects who were resistant to prior treatment with anti-CTLA-4 and/or anti-PD1/PD-L1 antibodies and those who lacked resistance in a subgroup analysis. This comparison is by necessity exploratory in nature and hypothesis generating.
Time frame: Up to 5 years
Analysis of Antibody Resistance: OS
Clinical outcomes such as OR, duration of response, CB, PFS, and OS will be analyzed separately among subjects who were resistant to prior treatment with anti-CTLA-4 and/or anti-PD1/PD-L1 antibodies and those who lacked resistance in a subgroup analysis. This comparison is by necessity exploratory in nature and hypothesis generating.
Time frame: Up to 5 years
Analysis of GD2+ vs GD2- Patients: OR
Clinical outcomes such as OR, duration of response, CB, PFS and OS and treatment associated selected biologic effects will be analyzed separately among patients who are GD2+ and those who are GD2- in a subgroup analysis. These outcome measures will be compared using two-sample t-test, log rank test and chi-square/Fisher's exact test between the two groups of patients who are GD2+ and who are GD2-.
Time frame: Up to 5 years
Analysis of GD2+ vs GD2- Patients: Duration of Response
Clinical outcomes such as OR, duration of response, CB, PFS and OS and treatment associated selected biologic effects will be analyzed separately among patients who are GD2+ and those who are GD2- in a subgroup analysis. These outcome measures will be compared using two-sample t-test, log rank test and chi-square/Fisher's exact test between the two groups of patients who are GD2+ and who are GD2-.
Time frame: Up to 5 years
Analysis of GD2+ vs GD2- Patients: CB
Clinical outcomes such as OR, duration of response, CB, PFS and OS and treatment associated selected biologic effects will be analyzed separately among patients who are GD2+ and those who are GD2- in a subgroup analysis. These outcome measures will be compared using two-sample t-test, log rank test and chi-square/Fisher's exact test between the two groups of patients who are GD2+ and who are GD2-.
Time frame: Up to 5 years
Analysis of GD2+ vs GD2- Patients: PFS
Clinical outcomes such as OR, duration of response, CB, PFS and OS and treatment associated selected biologic effects will be analyzed separately among patients who are GD2+ and those who are GD2- in a subgroup analysis. These outcome measures will be compared using two-sample t-test, log rank test and chi-square/Fisher's exact test between the two groups of patients who are GD2+ and who are GD2-.
Time frame: Up to 5 years
Analysis of GD2+ vs GD2- Patients: OS
Clinical outcomes such as OR, duration of response, CB, PFS and OS and treatment associated selected biologic effects will be analyzed separately among patients who are GD2+ and those who are GD2- in a subgroup analysis. These outcome measures will be compared using two-sample t-test, log rank test and chi-square/Fisher's exact test between the two groups of patients who are GD2+ and who are GD2-.
Time frame: Up to 5 years
PD-L1 Expression
PD-L1 expression level will be compared between baseline and after initiation of treatment using linear mixed effects model after suitable transformation of PD-L1 expression level. Clinical outcomes such as OR, duration of response, CB, PFS and OS and treatment associated selected biologic effects will be analyzed separately among patients who are PDL1+ and those who are PD-L1- in a subgroup analysis. In addition, these outcome measures will be compared using two-sample t-test, log rank test and chi-square/Fisher's exact test between the two groups of patients who are PD-L1+ and who are PD-L1-.
Time frame: up to 5 years

Results

Posted Jun 3, 2026

Participant flow

Phase 1A

Participant flow — Phase 1A
Milestone	Phase IA	Phase IB	Phase IC	Phase ID
Started	4	0	0	0
Completed treatment	4	0	0	0
On follow up	2	0	0	0
Completed	2	0	0	0
Not completed	2	0	0	0
Withdrew: Death	2	0	0	0

Phase IB

Participant flow — Phase IB
Milestone	Phase IA	Phase IB	Phase IC	Phase ID
Started	0	4	0	0
Completed treatment	0	3	0	0
Completed	0	3	0	0
Not completed	0	1	0	0
Withdrew: Withdrawal by subject	0	1	0	0

Phase IC

Participant flow — Phase IC
Milestone	Phase IA	Phase IB	Phase IC	Phase ID
Started	0	0	0	0
Completed	0	0	0	0
Not completed	0	0	0	0

Phase ID

Participant flow — Phase ID
Milestone	Phase IA	Phase IB	Phase IC	Phase ID
Started	0	0	0	0
Completed	0	0	0	0
Not completed	0	0	0	0

Outcome measures

PrimaryIncidence 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.

Time frame:: up to 2 years
Reported as:: Count of units · events

Incidence of Adverse Events
events	Phase IA	Phase IB	Phase IC	Phase ID
Grade 3	1	1	—	—
Grade 4	0	0	—	—
Grade 5	0	1	—	—

PrimaryMaximum 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.

Time frame:: up to 21 days
Reported as:: Number · milligrams per meter squared

Maximum Tolerated Dose (MTD)
milligrams per meter squared	Phase IA	Phase IB	Phase IC	Phase ID
Maximum Tolerated Dose (MTD)	2	NA	—	—

PrimaryMaximum 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.

Time frame:: up to 21 days
Reported as:: Number · milligrams per meter squared

Maximum Administered Dose (MAD)
milligrams per meter squared	Phase IA	Phase IB	Phase IC	Phase ID
Maximum Administered Dose (MAD)	2	1	—	—

SecondaryObjective Tumor Response (OR)

OR will be summarized using descriptive statistics. Furthermore, a point estimate along with the 95% confidence interval for the proportion of subjects with OR will be provided. Clinical outcome of OR will be summarized by dose level for Phase IC.

Time frame:: Up to 5 years

Results for this outcome have not been posted.

SecondaryProgression Free Survival (PFS)

The length of time from the start of treatment until disease progression or death. Kaplan-Meier method will be used to estimate the survival distribution of progression-free survival for the Phase ID expansion cohort.

Time frame:: Up to 5 years

Results for this outcome have not been posted.

SecondaryOverall Survival (OS)

The length of time from the start of treatment until death from any cause. Kaplan-Meier method will be used to estimate the survival distribution of overall survival for the Phase ID expansion cohort.

Time frame:: Up to 5 years

Results for this outcome have not been posted.

SecondaryClinical Benefit (CB)

The status of achieving complete response, partial response or stable disease in response to treatment.

Time frame:: Planned to be collected for up to 5 years, study closed early and this data was collected for approximately 8 months
Reported as:: Count of participants · Participants

Clinical Benefit (CB)
Participants	Phase IA	Phase IB	Phase IC	Phase ID
first assessment date, up to 3 months — Complete Response	0	0	—	—
first assessment date, up to 3 months — Stable Disease	1	1	—	—
first assessment date, up to 3 months — Disease Progression	3	1	—	—
first assessment date, up to 3 months — Mixed Response - Concern for Recurrence	0	0	—	—
second assessment date, up to 8 months — Complete Response	0	0	—	—
second assessment date, up to 8 months — Stable Disease	0	0	—	—
second assessment date, up to 8 months — Disease Progression	1	0	—	—
second assessment date, up to 8 months — Mixed Response - Concern for Recurrence	0	1	—	—

SecondaryDuration of Response

The length of time from documentation of tumor response until disease progression. Kaplan-Meier method will be used to estimate the survival distribution for the Phase ID expansion cohort.

Time frame:: Up to 5 years

Results for this outcome have not been posted.

SecondaryImmunologic Parameters: Change in Antibody Dependent Cell-Mediated Toxicity (ADCC) Function

Immunologic activation induced in vivo by intratumoral (IT)-hu14.18-IL2 fusion protein will be evaluated using both in vivo and in vitro analyses. Changes between assessment time points will be evaluated using a paired t-test or non-parametric Wilcoxon signed rank test, depending on the scale and distribution of the endpoint.

Time frame:: Baseline, Cycle 3 day 1, Cycle 5 day 1, End of Treatment (up to 13 cycles) (cycles 1-4 are 21 days, 5+ are 28 days)

Results for this outcome have not been posted.

SecondaryImmunologic Parameters: Change in Natural Killer (NK) Cell Function

Time frame:: Baseline, Cycle 3 day 1, Cycle 5 day 1, End of Treatment (up to 13 cycles) (cycles 1-4 are 21 days, 5+ are 28 days)

Results for this outcome have not been posted.

SecondaryImmunologic Parameters: Change in Soluble Interleukin-2 Receptor Alpha (IL-2 Alpha) Levels

Time frame:: Baseline; Cycle 1 days 1,4,8; Cycle 4 days 1,4,8; Cycle 7 days 1,4,8; Cycle 10 day 1,4,8 (cycles 1-4 are 21 days, 5+ are 28 days)

Results for this outcome have not been posted.

SecondaryHistological Parameters: Change in Necrotic Tumor Cells From Baseline

For the primary parameters to be assessed on the resected melanoma an objective scoring system will be established by a pathologist, grading each specimen with a score of 0, +, ++, +++. Changes in number of Necrotic Tumor Cells from baseline will be evaluated using a paired McNemar's test for binary outcomes. Quantitative assessment of necrosis of tumor cells will be measured and scored with a value ranging from 0% - 100% of tumor area.

Time frame:: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycles 1-4 are 21 days)

Results for this outcome have not been posted.

SecondaryHistological Parameters: Change in Apoptosis From Baseline

For the primary parameters to be assessed on the resected melanoma an objective scoring system will be established by a pathologist, grading each specimen with a score of 0, +, ++, +++.

Time frame:: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryHistological Parameters: Change in Inflammatory Infiltrate in the Tumor From Baseline

For the primary parameters to be assessed on the resected melanoma an objective scoring system will be established by a pathologist, grading each specimen with a score of 0, +, ++, +++.

Time frame:: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryHistological Parameters: Change in Cellular Phenotype of Infiltrate

Cellular phenotype of infiltrate within the tumor will be summarized by descriptive statistics. Changes from baseline will be evaluated using a paired McNemar's test for binary outcomes.

Time frame:: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryHistological Parameters: Change in hu14.18-IL2 in the Tumor From Baseline

Presence hu14.18-IL2 within the tumor will be summarized by descriptive statistics. Changes from baseline will be evaluated using a paired McNemar's test for binary outcomes.

Time frame:: Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryPharmacokinetic (PK) Parameters: Alpha Half-life

Pharmacokinetic assessments will be performed on multiple serum specimens for each subject. The analysis of all PK parameters will be performed using the PK analysis population. The distribution half-life called alpha half-life (t1/2 alpha) will be summarized by dose level with simple summary statistics.

Time frame:: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryPharmacokinetic (PK) Parameters: Beta Half-life

Pharmacokinetic assessments will be performed on multiple serum specimens for each subject. The analysis of all PK parameters will be performed using the PK analysis population. The elimination half-life called beta half-life (t1/2 beta) will be summarized by dose level with simple summary statistics.

Time frame:: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryPharmacokinetic (PK) Parameters: Area Under the Curve (AUC)

Pharmacokinetic assessments will be performed on multiple serum specimens for each subject. The analysis of all PK parameters will be performed using the PK analysis population. AUC will be summarized by dose level with simple summary statistics.

Time frame:: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryPharmacokinetic Parameters: Clearance (CL)

Pharmacokinetic assessments will be performed on multiple serum specimens for each subject. The analysis of all PK parameters will be performed using the PK analysis population. Clearance will be summarized by dose level with simple summary statistics.

Time frame:: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryPharmacokinetic (PK) Parameters: Relationship Between Dose and AUC

Scatterplots will be used to explore possible associations between the dose and area under the curve (AUC). The Jonckheere-Terpstra trend test will be performed to determine the significance of the association between increasing dose level and AUC.

Time frame:: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)

Results for this outcome have not been posted.

SecondaryPharmacokinetic (PK) Parameters: Relationship PK Parameters and Toxicity

Logistic regression analyses will be performed to correlate PK parameters with toxicity (grade \>= 3 vs. grade 0-2) and response.

Time frame:: At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days)

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of Antibody Resistance: OR

Clinical outcomes such as OR, duration of response, CB, PFS, and OS will be analyzed separately among subjects who were resistant to prior treatment with anti-CTLA-4 and/or anti-PD1/PD-L1 antibodies and those who lacked resistance in a subgroup analysis. This comparison is by necessity exploratory in nature and hypothesis generating.

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of Antibody Resistance: Duration of Response

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of Antibody Resistance: CB

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of Antibody Resistance: PFS

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of Antibody Resistance: OS

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of GD2+ vs GD2- Patients: OR

Clinical outcomes such as OR, duration of response, CB, PFS and OS and treatment associated selected biologic effects will be analyzed separately among patients who are GD2+ and those who are GD2- in a subgroup analysis. These outcome measures will be compared using two-sample t-test, log rank test and chi-square/Fisher's exact test between the two groups of patients who are GD2+ and who are GD2-.

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of GD2+ vs GD2- Patients: Duration of Response

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of GD2+ vs GD2- Patients: CB

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of GD2+ vs GD2- Patients: PFS

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedAnalysis of GD2+ vs GD2- Patients: OS

Time frame:: Up to 5 years

Results for this outcome have not been posted.

Other pre-specifiedPD-L1 Expression

PD-L1 expression level will be compared between baseline and after initiation of treatment using linear mixed effects model after suitable transformation of PD-L1 expression level. Clinical outcomes such as OR, duration of response, CB, PFS and OS and treatment associated selected biologic effects will be analyzed separately among patients who are PDL1+ and those who are PD-L1- in a subgroup analysis. In addition, these outcome measures will be compared using two-sample t-test, log rank test and chi-square/Fisher's exact test between the two groups of patients who are PD-L1+ and who are PD-L1-.

Time frame:: up to 5 years

Results for this outcome have not been posted.

Adverse events

Collected over up to 2 years. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Phase IA	2/4 (50%)	1/4 (25%)	4/4 (100%)
Phase IB	3/4 (75%)	2/4 (50%)	3/4 (75%)
Phase IC	—	—	—
Phase ID	—	—	—

Most frequent serious events

Most frequent serious events
Event	Phase IA	Phase IB	Phase IC	Phase ID
Injection Site ReactionGeneral disorders	1/4	0/4	—	—
HypotensionVascular disorders	0/4	1/4	—	—
Disease ProgressionHepatobiliary disorders	0/4	1/4	—	—

Most frequent other events

Showing 10 of 60

Most frequent other events
Event	Phase IA	Phase IB	Phase IC	Phase ID
ChillsGeneral disorders	4/4	2/4	—	—
Lymphocyte count decreasedInvestigations	4/4	2/4	—	—
NauseaGastrointestinal disorders	3/4	3/4	—	—
FatigueGeneral disorders	2/4	3/4	—	—
Injection site reactionGeneral disorders	3/4	2/4	—	—
HypotensionVascular disorders	3/4	3/4	—	—
VomitingGastrointestinal disorders	2/4	2/4	—	—
FeverGeneral disorders	2/4	1/4	—	—
Non-cardiac chest painGeneral disorders	2/4	0/4	—	—
Aspartate aminotransferase increasedInvestigations	2/4	2/4	—	—

Baseline characteristics

Study was closed to enrollment early per Sponsor

Age, Customized
Age, Customized(Participants)	Phase IA	Phase IB	Total
30 to 39 years	1	0	1
40 to 49 years	0	0	0
50 to 59 years	1	0	1
60 to 69 years	1	3	4
70 to 79 years	1	1	2

Sex: Female, Male
Sex: Female, Male(Participants)	Phase IA	Phase IB	Phase IC	Phase ID	Total
Female	1	3	0	0	4
Male	3	1	0	0	4

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Phase IA	Phase IB	Total
Hispanic or Latino	0	0	0
Not Hispanic or Latino	4	4	8
Unknown or Not Reported	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Phase IA	Phase IB	Total
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	0	0
White	4	4	8
More than one race	0	0	0
Unknown or Not Reported	0	0	0

Region of Enrollment
Region of Enrollment(participants)	Phase IA	Phase IB	Phase IC	Phase ID	Total
United States	4	4	—	—	8

Study locations

1 site

University of Wisconsin Carbone Cancer Center
Madison, Wisconsin 53792, United States

References and documents

Study documents

Protocol and statistical analysis plan · Jul 30, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Jun 3, 2026, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03958383
Lead sponsor: University of Wisconsin, Madison
Collaborators: National Cancer Institute (NCI), Bristol-Myers Squibb, AnYxis Immuno-Oncology GmbH, Provenance Biopharmaceuticals
Responsible party: Sponsor
First posted: May 22, 2019
Start date: Jan 30, 2020
Primary completion: Jan 6, 2024
Completion: Dec 9, 2025
Results posted: Jun 3, 2026
Last update: Jun 3, 2026

Study contacts

Paul Sondel, MD, PhD

principal investigator · University of Wisconsin, Madison

Mark R Albertini, MD

study chair · University of Wisconsin, Madison

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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

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