MSB0010445 and Stereotactic Body Radiation Therapy in Advanced Melanoma

Study Overview
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Brief Summary
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This is a Phase 2a, open-label, parallel group, partly randomized dose escalation trial to assess the safety and efficacy of a low dose, an intermediate dose, and high dose MSB0010445 given by intravenous infusion to subjects with advanced (unresectable or metastatic) melanoma in combination with stereotactic body radiation therapy (SBRT).

Official Title
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A Safety Study for MSB0010445 in Combination With Stereotactic Body Radiation in Advanced Melanoma Subjects Following Prior Treatment With Ipilimumab

Conditions
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Melanoma

Intervention / Treatment
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* Drug: MSB0010445 (0.3 milligram per kilogram [mg/kg])
* Drug: MSB0010445 (1.0 mg/kg)
* Drug: MSB0010445 (1.8 mg/kg)
* Drug: MSB0010445 (2.4 mg/kg)
* Radiation: Stereotactic Body Radiation Therapy (SBRT)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Advanced unresectable or metastatic melanoma, previously treated with ipilimumab; anti-melanoma treatments, including anti-PD/PD-L1 or any other immunotherapy, are allowed provided no treatment from last dose of that treatment to trial enrolment Subjects need to have one lesion that can be irradiated at least 1 measurable lesion outside the radiation field, different from the lesion that will be irradiated one lesion that can be biopsied before treatment with SBRT and MSB0010445 one lesion outside the radiation field that can be biopsied while on treatment with MSB0010445 The lesion that is biopsied at Baseline can be the lesion that will be irradiated The lesion that will be biopsied while on treatment should not be a lesion that has been irradiated or biopsied at Baseline Signed written informed consent Male and female subjects at least 18 years of age Life expectancy greater than or equal to (>=) 4 months Eastern cooperative oncology group (ECOG) performance status of 0 or 1 Other protocol defined inclusion criteria could apply Exclusion Criteria: Active central nervous system metastasis Treatment with systemic anti-cancer therapy within the 30 days before the first dose of SBRT Pre-existing pericardial effusion or history of Grade >=2 pleural effusion or ascites within 3 months before first dose of SBRT Concurrent systemic therapy with steroids or other immunosuppressive agents except short-term systemic steroids for allergic reactions Other protocol defined exclusion criteria could apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MSB0010445 Low Dose Cohort 0.3 mg/kg<br> | Drug: MSB0010445 (0.3 milligram per kilogram [mg/kg])<br>* MSB0010445 will be administered at a single dose of 0.3 mg/kg as intravenous (IV) infusion over approximately 1 hour every 3 weeks (q3w) for the first 12 Weeks as a part of induction phase followed by maintenance dose of 0.3 mg/kg drug every three weeks until significant clinical progression, occurrence of unacceptable toxicity, or withdrawal of consent. The first administration of MSB0010445 will be performed 3 days after the last dose of Stereotactic Body Radiation Therapy (SBRT) to the targeted reference lesion.<br>Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* SBRT will be administered using a dose and schedule recommended based upon the data showing the best abscopal effect using multiple fractions if one site will be targeted subject received 3 fractions (1 per day) of 8 Gray (Gy) each (total: 24 Gy). If the target lesion will be located in the thorax, the maximum total dose administered will be 18 Gy (3 x 6 Gy).<br>|
| Experimental: MSB0010445 Intermediate Dose Cohort 1.0 mg/kg<br> | Drug: MSB0010445 (1.0 mg/kg)<br>* MSB0010445 will be administered at a single dose of 1.0 mg/kg as IV infusion over approximately 1 hour q3w for the first 12 Weeks as a part of induction phase followed by maintenance dose of 0.3 mg/kg drug every three weeks until significant clinical progression, occurrence of unacceptable toxicity, or withdrawal of consent. The first administration of MSB0010445 will be performed 3 days after the last dose of SBRT to the targeted reference lesion.<br>Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* SBRT will be administered using a dose and schedule recommended based upon the data showing the best abscopal effect using multiple fractions if one site will be targeted subject received 3 fractions (1 per day) of 8 Gray (Gy) each (total: 24 Gy). If the target lesion will be located in the thorax, the maximum total dose administered will be 18 Gy (3 x 6 Gy).<br>|
| Experimental: MSB0010445 High Dose Cohort 1.8 mg/kg<br> | Drug: MSB0010445 (1.8 mg/kg)<br>* MSB0010445 will be administered at a single dose of 1.8 mg/kg as IV infusion over approximately 1 hour q3w for the first 12 Weeks as a part of induction phase followed by maintenance dose of 0.3 mg/kg drug every three weeks until significant clinical progression, occurrence of unacceptable toxicity, or withdrawal of consent. The first administration of MSB0010445 will be performed 3 days after the last dose of SBRT to the targeted reference lesion.<br>Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* SBRT will be administered using a dose and schedule recommended based upon the data showing the best abscopal effect using multiple fractions if one site will be targeted subject received 3 fractions (1 per day) of 8 Gray (Gy) each (total: 24 Gy). If the target lesion will be located in the thorax, the maximum total dose administered will be 18 Gy (3 x 6 Gy).<br>|
| Experimental: MSB0010445 High Dose Cohort 2.4 mg/kg<br> | Drug: MSB0010445 (2.4 mg/kg)<br>* MSB0010445 will be administered at a single dose of 2.4 mg/kg as IV infusion over approximately 1 hour q3w for the first 12 Weeks as a part of induction phase followed by maintenance dose of 0.3 mg/kg drug every three weeks until significant clinical progression, occurrence of unacceptable toxicity, or withdrawal of consent. The first administration of MSB0010445 will be performed 3 days after the last dose of SBRT to the targeted reference lesion.<br>Radiation: Stereotactic Body Radiation Therapy (SBRT)<br>* SBRT will be administered using a dose and schedule recommended based upon the data showing the best abscopal effect using multiple fractions if one site will be targeted subject received 3 fractions (1 per day) of 8 Gray (Gy) each (total: 24 Gy). If the target lesion will be located in the thorax, the maximum total dose administered will be 18 Gy (3 x 6 Gy).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With at Least 1 Dose Limiting Toxicity (DLT) | DLT was defined as any Grade>= 3 toxicity related to drug, occurring during 21 days post first dose of drug except Grade 3 infusion-related adverse reaction resolving within 6 hours and Transient (<=6 hours) Grade 3 flu-like symptoms/fever controlled with medical management; Transient (<= 24 hours) Grade 3 fatigue, local reactions, headache, nausea, emesis that resolved to <= Grade 1; Grade 3 skin toxicity ,Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 8 x upper limit of normal (ULN)/total bilirubin < 5 x ULN resolving to <= Grade 1 in <7 days after medical management; Grade 3 diarrhea controlled with maximal medical management within 72 hours; Grade 4 lymphopenia that resolves to <= Grade 1 within 7 days & with no clinical manifestations; Grade 3 lab abnormality with no clinical correlation and resolves to <= Grade 1 within 7 days with adequate medical management Tumor flare defined as local pain, irritation or rash localized at sites of known/suspected tumor. | Baseline up to Day 21 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | BOR was defined as a confirmed complete response (CR) or partial response (PR) during second-line treatment. For target lesions (TLs), CR was defined as the disappearance of all TLs, and PR was defined as at least a 30% decrease in the SLD of the TLs, taking as a reference the baseline SLD. For non-target lesions (NTLs), CR was defined as the disappearance of all NTLs and normalization of tumor marker levels. | Screening up to 28 days after last dose of drug; assessed up to maximum of 1.41 years | 
| Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | TEAE was defined as an AE that started on or after the first administration of SBRT. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/ significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. | Screening up to 28 days after last dose of drug; assessed up to maximum of 1.41 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Melanoma, MSB0010445, Dose limiting toxicity, Stereotactic body radiation therapy