Phase I/II Intratumoral Administration of Hu14.18-IL2, With Local Radiation, Nivolumab and Ipilimumab in Subjects With Advanced Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 8
- 试验地点
- 1
- 主要终点
- Maximum Administered Dose (MAD)
研究概览
简要总结
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.
详细描述
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)
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •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.
研究组 & 干预措施
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.
干预措施: Ipilimumab (Biological)
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.
干预措施: hu14.18-IL2 (Biological)
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.
干预措施: Radiation Therapy (Radiation)
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.
干预措施: Nivolumab (Biological)
结局指标
主要结局
Maximum Administered Dose (MAD)
时间窗: up to 21 days
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.
Maximum Tolerated Dose (MTD)
时间窗: up to 21 days
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.
Incidence of Adverse Events
时间窗: up to 2 years
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.
次要结局
- Objective Tumor Response (OR)(Up to 5 years)
- Overall Survival (OS)(Up to 5 years)
- Histological Parameters: Change in Cellular Phenotype of Infiltrate(Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days))
- Immunologic Parameters: Change in Natural Killer (NK) Cell Function(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))
- Progression Free Survival (PFS)(Up to 5 years)
- Immunologic Parameters: Change in Antibody Dependent Cell-Mediated Toxicity (ADCC) Function(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))
- Pharmacokinetic Parameters: Clearance (CL)(At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days))
- Duration of Response(Up to 5 years)
- Pharmacokinetic (PK) Parameters: Area Under the Curve (AUC)(At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days))
- Clinical Benefit (CB)(Planned to be collected for up to 5 years, study closed early and this data was collected for approximately 8 months)
- Immunologic Parameters: Change in Soluble Interleukin-2 Receptor Alpha (IL-2 Alpha) Levels(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(Baseline, Cycle 1, Cycle 2, Cycle 4 (cycles 1-4 are 21 days))
- Histological Parameters: Change in Apoptosis From Baseline(Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days))
- Histological Parameters: Change in Inflammatory Infiltrate in the Tumor From Baseline(Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days))
- Histological Parameters: Change in hu14.18-IL2 in the Tumor From Baseline(Baseline, Cycle 1, Cycle 2, Cycle 4 (cycle length is 21 days))
- Pharmacokinetic (PK) Parameters: Alpha Half-life(At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days))
- Pharmacokinetic (PK) Parameters: Beta Half-life(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(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(At baseline, course 1 day 5, and day 5 of courses 2 & 4 (cycle length is 21 days))