Pembrolizumab and Hypofractionated Stereotactic Radiother... | NCT04166734

Name	Class
Merck Sharp & Dohme LLC	INDUSTRY

Description Module

Detailed Description

The study will be conducted in two parts; an initial safety phase (Part A), followed by an expansion cohort (Part B). The initial safety phase (Part A) is based on a 3+3 design such that patients will be treated in a cohort of 3-6 patients. A maximum of 6 patients will be allocated to Part A exploring SBRT 30 Gy in 3 fractions in combination with pembrolizumab. If there is more than one DLT in the first 3 patients or two or more DLTs in the first 6 patients, this treatment combination will be deemed as being unacceptable and it would lead to termination of the study. During the expansion cohort (Part B), 12 patients will have SBRT 30 Gy in 3 fractions with pembrolizumab to obtain additional safety and response data. Maintenance pembrolizumab will continue until disease progression, unacceptable toxicities, the patient withdraws consent to the trial, or the patient has completed 35 cycles of treatment. A maximum of 18 patients will be treated in the study.

All patients will receive pembrolizumab on cycle (C) 1 day (D) 1, in Part A and B of the study. All patients will receive SBRT on C1D15, C1D17 and C1D19, as per SBRT protocol. Patients in part A will receive SBRT 30 Gy in 3#. Patients in Part B will receive 30 Gy in 3 fractions if considered safe after part A. All patients in Part A and Part B will receive pembrolizumab dosed at 200 mg every 3 weeks, until disease progression, unacceptable toxicities, the patient withdraws consent from the trial or the patient has completed 35 cycles of treatment.

In the initial safety cohort, a minimum of 3 patients will be treated at the SBRT dose of 30Gy in 3 fractions combined with pembrolizumab. The gap left between the treatments of each subsequent patient will start after the second cycle of Pembrolizumab in the previous dosed patient to mitigate against multiple patients suffering from acute toxicity. The DLT period for this study is 12 weeks from the last dose of SBRT (i.e. at C6D1). Patients included in Part A will be considered by the Safety Review Committee (SRC) once the 3rd and 6th patient in the Part A cohort has completed the DLT period. If 0 out of 3 patients experience a DLT, or if 1 out of 3 patients experience a DLT in Part A, then the cohort will be expanded to 6 patients. If 1 in 6 patients experience a DLT, then it will be acceptable to move forward to the expansion cohort (Part B).

However, if ≥ 2 in 6 patients (or more than 1 in the first 3 patients) experience a DLT then the maximum administered dose (MAD) will have been reached. If the MAD is seen at a dose level of 30 Gy in 3# then the study will be terminated.

While waiting for 3 or 6 patients to complete the DLT period, no additional patients will be recruited. Further patients can only be recruited after the SRC has reviewed the toxicity data for the cohort to proceed to Part B. Patients obtaining complete response or having completed 35 cycles of pembrolizumab must discontinue and may recommence for additional 17 cycles upon subsequent disease, the CI/PI will need to discuss with the sponsor and MSD, on a case by case basis for the continuation of pembrolizumab

Label	Type	Description	Intervention Names
Initial safety cohort	Other	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks.	Drug: Pembrolizumab Radiation: Stereotactic Body Radiotherapy (SBRT)
Expansion cohort	Other	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks.	Drug: Pembrolizumab Radiation: Stereotactic Body Radiotherapy (SBRT)

Name	Type	Description	Arm Group Labels	Other Names
Pembrolizumab	Drug	Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks.

Measure	Description	Time Frame
Percentage of Patients With Dose Limiting Toxicity (DLT)	Dose limiting toxicity is assessed using CTCAE v5.0 and defined as any one of: neutropenia with fever grade>=3; neutropenia grade>=4; thrombocytopenia with bleeding grade >=3; thrombocytopenia grade >=4; any non-haematological toxicity grade >=3 which is definitely, probably or possibly related to the combination of pembrolizumab and SBRT	Worst grade as assessed at cycle 1 day 1 of pembrolizumab, at each of three radiotherapy fractions (cycle 1 days 15, 17, 19) and then at day 1 of each 21 day cycle, up to 12 weeks from last dose of SBRT (i.e. cycle 6 day 1)

Measure	Description	Time Frame
Worst Acute Toxicity Grade	Number of patients by worst recorded grade of acute toxicity, assessed using CTCAE v5.0	Worst grade as assessed at cycle 1 day 1 of pembrolizumab, at each of three radiotherapy fractions (cycle 1 days 15, 17, 19) and then at day 1 of each 21 day cycle, up to 12 weeks from last dose of SBRT (i.e. cycle 6 day 1)

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Patients should be ≥18 years old on the day of signing the informed consent.
Patients must have a histological or cytological diagnosis of MPM.
Patients should have non-radically treatable MPM (i.e. not being considered for extrapleural pneumonectomy or pleurectomy and decortication).
Patients must have measurable disease as assessed by mRECIST (i.e. at least a 1 cm rind of MPM at 2 sites on 3 different levels).
Patients must have had disease progression or be intolerant of standard first-line palliative chemotherapy for MPM. Patients who have declined first-line palliative chemotherapy must have been suitable for platinum-doublet combination chemotherapy.
Patient should have an ECOG performance status 0-1.
Patients should be able to tolerate a course of stereotactic radiotherapy as assessed by the investigator.
Patients should have pleural based disease, away from critical structures, and suitable for treatment to part of lesion with SBRT for pleural mesothelioma.
Patients must have adequate organ function including MRC dyspnoea score <3 and adequate baseline lung function tests, with an FEV1 > 0.8L or >30% of predicted and a TLCO > 30%.
Demonstrate adequate organ function (based on bloods within 10 days of C1D1).
Have provided tissue from an archival tissue sample or newly obtained tissue sample.
Female patient of childbearing potential should have a negative serum pregnancy within 72 hours prior to receiving the first dose of study medication (C1D1). Female patients of childbearing potential should be willing to use highly effective methods of contraception for the course of the study through 120 days after the last dose of study medication. Female of childbearing potential is defined as women following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.
Male patients should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Be willing to provide informed consent for the trial.

Exclusion criteria

Patients who have taken any investigational medicinal product or have used an investigational device within 4 weeks of the first dose of pembrolizumab. Patients are allowed to participate in additional observational studies.
Patients who have received prior chemotherapy, targeted small molecule therapy or radiotherapy within 4 weeks prior to the first dose of pembrolizumab.
Patients with a diagnosis of immunodeficiency or be receiving systemic steroid therapy (>7.5 mg of prednisone / >1 mg of dexamethasone or their equivalent dose) or any other form of immunosuppressive therapy within 7 days prior to the first dose.
Patients with evidence of active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents or an autoimmune disease that is currently quiescent off any treatment, but deemed at risk of a significant flare if treated on this protocol.
Patients who have received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
Patients with evidence of active central nervous system (CNS) metastases and/or carcinomatous meningitis. Patients with previously treated brain metastases may participate provided the brain metastases are stable and there is no evidence of new or enlarging brain metastases.
Patients who have had previous radiotherapy to the thorax or other neighbouring region that would preclude the safe administration of SBRT for MPM.
Patients with evidence of interstitial lung disease or active, non-infectious pneumonitis.
Patients with evidence of additional malignancy that is progressing or requires active treatment.
Patients with a history or current evidence of any condition, therapy, or laboratory abnormality that might confound trial results, interfere with the patient's participation or is not in the best interest of the patient.
Patients with psychiatric or substance abuse disorders that would interfere with patients participation.
Patients who are pregnant / breastfeeding or expecting to conceive within the duration of the trial, starting with the screening visit through 120 days after the last dose.
Patients with a history of HIV, HIV 1/2 antibodies, Hepatitis B or Hepatitis C.
Patients with any active infection requiring systemic treatment
Patients who have received a live vaccine within 30 days prior to the first dose of trial treatment.
Patients with known hypersensitivity to the active substance pembrolizumab or to any of the excipients listed in the IB.

Name	Affiliation	Role
Fiona McDonald	Royal Marsden NHS Foundation Trust	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Royal Marsden NHS Foundation Trust		Chelsea			United Kingdom
Beatson West of Scotland Cancer Centre

ID	Title	Description
FG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 13, 2020	Jun 28, 2024

ID	Title	Description
BG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
BG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG0005 BG0010 BG0025

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percentage of Patients With Dose Limiting Toxicity (DLT)

Dose limiting toxicity is assessed using CTCAE v5.0 and defined as any one of: neutropenia with fever grade>=3; neutropenia grade>=4; thrombocytopenia with bleeding grade >=3; thrombocytopenia grade >=4; any non-haematological toxicity grade >=3 which is definitely, probably or possibly related to the combination of pembrolizumab and SBRT

Patients who remained on trial for the duration of the DLT time frame

Posted

Count of Participants

Participants

Worst grade as assessed at cycle 1 day 1 of pembrolizumab, at each of three radiotherapy fractions (cycle 1 days 15, 17, 19) and then at day 1 of each 21 day cycle, up to 12 weeks from last dose of SBRT (i.e. cycle 6 day 1)

ID	Title	Description
OG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
OG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Units	Counts
Participants	OG0003 OG0010

Title

Denominators

Categories

Title	Measurements
	OG0000

Secondary

Worst Acute Toxicity Grade

Number of patients by worst recorded grade of acute toxicity, assessed using CTCAE v5.0

All patients who received at least one dose of trial treatment

Posted

Count of Participants

Participants

ID	Title	Description
OG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
OG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Secondary

Overall Response Rate

Proportion of patients with best recorded response as assessed using RECIST v1.1 of complete or partial response

All patients who commenced trial treatment and who were assessed at least once for response

Posted

Count of Participants

Participants

Response assessed from start of pembrolizumab, every 9 weeks for the first 6 months, then every 12 weeks thereafter, until the first instance of documented disease progression, start of new anti-cancer treatment, death or end of study (24 months)

ID	Title	Description
OG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
OG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Secondary

Disease Control Rate

Proportion of patients with best recorded response as assessed using RECIST v1.1 of complete or partial response or stable disease

All patients who commenced trial treatment and who were assessed at least once for response

Posted

Count of Participants

Participants

ID	Title	Description
OG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
OG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Secondary

Overall Survival (OS) at Six Months

Proportion of patients alive at six months

All patients who commenced trial treatment and did not withdraw before 6 months

Posted

Count of Participants

Participants

6 months after start of pembrolizumab treatment

ID	Title	Description
OG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
OG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Secondary

Overall Survival (OS) at Twelve Months

Proportion of patients alive at twelve months

All patients who commenced trial treatment and did not withdraw before 12 months

Posted

Count of Participants

Participants

12 months after start of pembrolizumab treatment

ID	Title	Description
OG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
OG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Secondary

Progression Free Survival at 6 Months

Proportion of patients alive and free from progression at six months

Patients who commenced trial treatment and did not withdraw before progression and before 6 months

Posted

Count of Participants

Participants

6 months after commencing pembrolizumab treatment

ID	Title	Description
OG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
OG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Secondary

Progression Free Survival at 12 Months

Proportion of patients alive and free from progression at twelve months

Patients who commenced trial treatment and did not withdraw before progression and before 12 months

Posted

Count of Participants

Participants

12 months after commencing pembrolizumab treatment

ID	Title	Description
OG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)
OG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Dyspnea	Respiratory, thoracic and mediastinal disorders	CTCAE (5.0)	Systematic Assessment	EG0004 events3 affected5 at risk EG0010 at risk
Lethargy	Nervous system disorders	CTCAE (5.0)	Systematic Assessment	EG0004 events3 affected5 at risk EG0010 at risk
Weight loss	Investigations	CTCAE (5.0)	Systematic Assessment	EG0004 events3 affected5 at risk EG0010 at risk
Alanine aminotransferase increased	Investigations	CTCAE (5.0)	Systematic Assessment	EG0004 events2 affected5 at risk EG0010 at risk
Anorexia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment	EG0002 events2 affected5 at risk EG0010 at risk
Aspartate aminotransferase increased	Investigations	CTCAE (5.0)	Systematic Assessment	EG0004 events2 affected5 at risk EG0010 at risk
Constipation	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment	EG0002 events2 affected5 at risk EG0010 at risk
Cough	Respiratory, thoracic and mediastinal disorders	CTCAE (5.0)	Systematic Assessment	EG0004 events2 affected5 at risk EG0010 at risk
Diarrhea	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment	EG0002 events2 affected5 at risk EG0010 at risk
Fatigue	General disorders	CTCAE (5.0)	Systematic Assessment	EG0003 events2 affected5 at risk EG0010 at risk
Fever	General disorders	CTCAE (5.0)	Systematic Assessment	EG0002 events2 affected5 at risk EG0010 at risk
Alkaline phosphatase increased	Investigations	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Anemia	Blood and lymphatic system disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Anxiety	Psychiatric disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Arthritis	Musculoskeletal and connective tissue disorders	CTCAE (5.0)	Systematic Assessment	EG0003 events1 affected5 at risk EG0010 at risk
Back pain	Musculoskeletal and connective tissue disorders	CTCAE (5.0)	Systematic Assessment	EG0002 events1 affected5 at risk EG0010 at risk
Blood lactate dehydrogenase increased	Investigations	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Chest wall pain	Musculoskeletal and connective tissue disorders	CTCAE (5.0)	Systematic Assessment	EG0002 events1 affected5 at risk EG0010 at risk
Dry mouth	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Dysphagia	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Erythroderma	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Flu like symptoms	General disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Generalized muscle weakness	Musculoskeletal and connective tissue disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Hyperhidrosis	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Hyperphosphatemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Hypertension	Vascular disorders	CTCAE (5.0)	Systematic Assessment	EG0004 events1 affected5 at risk EG0010 at risk
Hyperuricemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Hypoalbuminemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Hypocalcemia	Metabolism and nutrition disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Investigations - other, increased C-reactive protein	Investigations	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Investigations - other, increased lactate	Investigations	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Insomnia	Psychiatric disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Lung infection	Infections and infestations	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Lymphocyte count decreased	Investigations	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Papilledema	Eye disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	CTCAE (5.0)	Systematic Assessment	EG0003 events1 affected5 at risk EG0010 at risk
Rash maculo-papular	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment	EG0002 events1 affected5 at risk EG0010 at risk
Rhinorrhea	Respiratory, thoracic and mediastinal disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Skin atrophy	Skin and subcutaneous tissue disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Vomiting	Gastrointestinal disorders	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk
Investigations - other, raised urea	Investigations	CTCAE (5.0)	Systematic Assessment	EG0001 events1 affected5 at risk EG0010 at risk

ID	Term
D000236	Adenoma
D009375	Neoplasms, Glandular and Epithelial
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D018301	Neoplasms, Mesothelial

ID	Term
D011878	Radiotherapy
D013812	Therapeutics
D013238	Stereotaxic Techniques
D019635	Neurosurgical Procedures
D013514	Surgical Procedures, Operative
D008919	Investigative Techniques

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Initial Safety Cohort	Patients will receive an initial dose of pembrolizumab in week 1 dosed at 200 mg. They will then receive SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)	2	5	3	5	5	5
EG001	Expansion Cohort	An additional 12 patients will be recruited for this cohort. Patients will receive an initial dose of pembrolizumab at 200 mg in week 1. This will be followed in by SBRT dosed at 30 Gy in 3 fractions (#) alternate days in week 3. Treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Pembrolizumab: Pembrolizumab will be continued dosed at 200 mg given every 3 weeks Drug: Pembrolizumab Pembrolizumab in week 1 dosed at 200 mg (prior to SBRT) and then treatment with pembrolizumab will be continued dosed at 200 mg given every 3 weeks. Stereotactic Body Radiotherapy (SBRT): Stereotactic Body Radiotherapy (SBRT) 30 Gy 3 fractions (#)	0	0	0	0	0	0