Melanoma
Conditions
Keywords
Melanoma, MSB0010445, Dose limiting toxicity, Stereotactic body radiation therapy
Brief summary
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).
Interventions
DRUGMSB0010445 (0.3 milligram per kilogram [mg/kg])
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.
DRUGMSB0010445 (1.0 mg/kg)
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.
DRUGMSB0010445 (1.8 mg/kg)
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.
DRUGMSB0010445 (2.4 mg/kg)
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.
RADIATIONStereotactic Body Radiation Therapy (SBRT)
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).
Sponsors
Merck KGaA, Darmstadt, Germany
EMD Serono
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With at Least 1 Dose Limiting Toxicity (DLT) | Baseline up to Day 21 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | Screening up to 28 days after last dose of drug; assessed up to maximum of 1.41 years | 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. |
| Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Screening up to 28 days after last dose of drug; assessed up to maximum of 1.41 years | 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. |
Countries
United States
Participant flow
Recruitment details
First/Last subject (informed consent): 24 January 2014/17 December 2014. Study completion date:10 June 2015. The study was conducted at 6 sites in the United States.
Participants by arm
| Arm | Count |
|---|---|
| MSB0010445 Low Dose Cohort 0.3 mg/kg MSB0010445 was administered at a dose of 0.3 mg/kg as IV infusion over approximately 1 hour q3w until significant clinical progression, occurrence of unacceptable toxicity, or withdrawal of consent. The first administration of MSB0010445 was performed 3 days after the last dose of SBRT to the targeted reference lesion. SBRT was administered using a dose and schedule recommended based upon the data showing the best abscopal effect using multiple fractions. One site was targeted and was received 3 fractions (1 per day) of 8 Gy each (total: 24 Gy). If the target lesion was located in the thorax, the maximum total dose was 18 Gy (3 x 6 Gy). | 2 |
| MSB0010445 Intermediate Dose Cohort 1.0 mg/kg MSB0010445 was administered at a dose of 1.0 mg/kg as IV infusion over approximately 1 hour q3w until significant clinical progression, occurrence of unacceptable toxicity, or withdrawal of consent. The first administration of MSB0010445 was performed 3 days after the last dose of SBRT to the targeted reference lesion. SBRT was administered using a dose and schedule recommended based upon the data showing the best abscopal effect using multiple fractions. One site was targeted and was received 3 fractions (1 per day) of 8 Gy each (total: 24 Gy). If the target lesion was located in the thorax, the maximum total dose was 18 Gy (3 x 6 Gy). | 2 |
| MSB0010445 High Dose Cohort 1.8 mg/kg MSB0010445 was administered at a dose of 1.8 mg/kg as IV infusion over approximately 1 hour q3w until significant clinical progression, occurrence of unacceptable toxicity, or withdrawal of consent. The first administration of MSB0010445 was performed 3 days after the last dose of SBRT to the targeted reference lesion. SBRT was administered using a dose and schedule recommended based upon the data showing the best abscopal effect using multiple fractions. One site was targeted and was received 3 fractions (1 per day) of 8 Gy each (total: 24 Gy). If the target lesion was located in the thorax, the maximum total dose was 18 Gy (3 x 6 Gy). | 6 |
| MSB0010445 High Dose Cohort 2.4 mg/kg MSB0010445 was administered at a dose of 2.4 mg/kg as IV infusion over approximately 1 hour q3w until significant clinical progression, occurrence of unacceptable toxicity, or withdrawal of consent. The first administration of MSB0010445 was performed 3 days after the last dose of SBRT to the targeted reference lesion. SBRT was administered using a dose and schedule recommended based upon the data showing the best abscopal effect using multiple fractions. One site was targeted and was received 3 fractions (1 per day) of 8 Gy each (total: 24 Gy). If the target lesion was located in the thorax, the maximum total dose was 18 Gy (3 x 6 Gy). | 2 |
| Total | 12 |
Baseline characteristics
| Characteristic | MSB0010445 Low Dose Cohort 0.3 mg/kg | MSB0010445 Intermediate Dose Cohort 1.0 mg/kg | MSB0010445 High Dose Cohort 1.8 mg/kg | MSB0010445 High Dose Cohort 2.4 mg/kg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.12 years STANDARD_DEVIATION 13.48 | 59.55 years STANDARD_DEVIATION 4.11 | 59.67 years STANDARD_DEVIATION 6.29 | 53.78 years STANDARD_DEVIATION 20.03 | 57.91 years STANDARD_DEVIATION 8.9 |
| Sex: Female, Male Female | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 4 Participants | 1 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 2 / 2 | 6 / 6 | 2 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 3 / 6 | 1 / 2 |
Outcome results
Primary
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.
Time frame: Baseline up to Day 21
Population: Safety analysis set included all subjects who signed informed consent, were enrolled into the study and received at least 1 dose of MSB0010445.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MSB0010445 Low Dose Cohort 0.3 mg/kg | Number of Subjects With at Least 1 Dose Limiting Toxicity (DLT) | 0 subjects |
| MSB0010445 Intermediate Dose Cohort 1.0 mg/kg | Number of Subjects With at Least 1 Dose Limiting Toxicity (DLT) | 0 subjects |
| MSB0010445 High Dose Cohort 1.8 mg/kg | Number of Subjects With at Least 1 Dose Limiting Toxicity (DLT) | 1 subjects |
| MSB0010445 High Dose Cohort 2.4 mg/kg | Number of Subjects With at Least 1 Dose Limiting Toxicity (DLT) | 0 subjects |
Secondary
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.
Time frame: Screening up to 28 days after last dose of drug; assessed up to maximum of 1.41 years
Population: Safety analysis set included all subjects who signed informed consent, were enrolled into the study and received at least 1 dose of MSB0010445. Here Number of Participants Analyzed signifies those subjects who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MSB0010445 Low Dose Cohort 0.3 mg/kg | Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | PR | 0 subjects |
| MSB0010445 Low Dose Cohort 0.3 mg/kg | Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | CR | 0 subjects |
| MSB0010445 Intermediate Dose Cohort 1.0 mg/kg | Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | CR | 0 subjects |
| MSB0010445 Intermediate Dose Cohort 1.0 mg/kg | Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | PR | 0 subjects |
| MSB0010445 High Dose Cohort 1.8 mg/kg | Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | CR | 0 subjects |
| MSB0010445 High Dose Cohort 1.8 mg/kg | Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | PR | 0 subjects |
| MSB0010445 High Dose Cohort 2.4 mg/kg | Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | PR | 0 subjects |
| MSB0010445 High Dose Cohort 2.4 mg/kg | Number of Subjects With Best Overall Response (BOR) According to Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1 | CR | 0 subjects |
Secondary
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.
Time frame: Screening up to 28 days after last dose of drug; assessed up to maximum of 1.41 years
Population: Safety analysis set included all subjects who signed informed consent, were enrolled into the study and received at least 1 dose of MSB0010445.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MSB0010445 Low Dose Cohort 0.3 mg/kg | Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Treatment Emergent Adverse Events | 2 subjects |
| MSB0010445 Low Dose Cohort 0.3 mg/kg | Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Serious AEs | 0 subjects |
| MSB0010445 Intermediate Dose Cohort 1.0 mg/kg | Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Treatment Emergent Adverse Events | 2 subjects |
| MSB0010445 Intermediate Dose Cohort 1.0 mg/kg | Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Serious AEs | 0 subjects |
| MSB0010445 High Dose Cohort 1.8 mg/kg | Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Treatment Emergent Adverse Events | 6 subjects |
| MSB0010445 High Dose Cohort 1.8 mg/kg | Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Serious AEs | 3 subjects |
| MSB0010445 High Dose Cohort 2.4 mg/kg | Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Treatment Emergent Adverse Events | 2 subjects |
| MSB0010445 High Dose Cohort 2.4 mg/kg | Number of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious AEs | Serious AEs | 1 subjects |