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

 -  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.