Advanced Malignant Solid Neoplasm, Castration-Resistant Prostate Carcinoma, Malignant Solid Neoplasm, Metastatic Malignant Solid Neoplasm, Metastatic Prostate Carcinoma, Prostate Carcinoma Metastatic in the Bone, Refractory Malignant Solid Neoplasm, Stage IV Prostate Cancer AJCC v8, Stage IVA Prostate Cancer AJCC v8, Stage IVB Prostate Cancer AJCC v8
Conditions
Brief summary
This phase I/II trial studies the side effects of avelumab when given in different combinations with utomilumab, anti-OX40 antibody PF-04518600, and radiation therapy in treating patients with malignancies that have spread to other places in the body (advanced). Immunotherapy with monoclonal antibodies, such as avelumab, utomilumab, and anti-OX40 antibody PF-04518600, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high-energy rays to kill tumor cells and shrink tumors. It is not yet known how well avelumab works in combination with these other anti-cancer therapies in patients with advanced malignancies.
Detailed description
PRIMARY OBJECTIVES: I. For Arm D, to establish the safety, tolerability, and dose-limiting toxicities (DLTs) of different treatment combinations of avelumab when administered in combination with a checkpoint agonist with radiation in patients with metastatic solid tumors in order to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). II. To correlate pre- and post-treatment CD8 expression with clinical benefit (complete response \[CR\], partial response \[PR\], or stable disease \[SD\] for \> 6 months). SECONDARY OBJECTIVES: I. To evaluate the efficacy of the different treatment combinations in patients with metastatic solid tumors by assessing objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune-related RECIST (irRECIST). II. To evaluate the efficacy of the different treatment combinations in patients with metastatic solid tumors by assessing progression-free survival (PFS), duration of response (DOR), and overall survival (OS). EXPLORATORY OBJECTIVES: I. To understand the mechanism of action of the avelumab plus an immune modulator combination, as well as potential mechanisms of resistance. II. To characterize the effect of avelumab combinations on immune biomarkers in peripheral blood and tumor tissue obtained from subjects pre- and post-treatment. III. To compare the response in irradiated versus non-irradiated lesions in Arm D. IV. To investigate immune biomarkers that are potentially predictive of response and resistance with the combination of avelumab and an immune modulator. OUTLINE: Patients are assigned to 1 of 6 arms. ARM A: Patients receive utomilumab intravenously (IV) over 60 minutes on day 1 of each cycle and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15 of each cycle and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15 of each cycle, utomilumab over 60 minutes on day 1, and avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM D: Patients undergo radiation therapy on days -5 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 of beginning day 15 of cycle 1 and utomilumab IV over 60 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM E: DISCONTINUED AS OF AMENDMENT 9 (02/11/2020) Patients undergo radiation therapy on days -14 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1 and anti-OX40 agonist monoclonal antibody PF-04518600 IV over 60 minutes on days 1 and 15, and. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM F: DISCONTINUED AS OF AMENDMENT 9 (02/11/2020) Patients undergo radiation therapy on days -14 to -1. Patients receive avelumab IV over 60 minutes on days 1 and 15 beginning day 15 of cycle 1, utomilumab IV over 60 minutes on day 1, and anti-OX40 agonist monoclonal antibody PF-04518600 IV on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients will be followed up at 30 days and then every 12 weeks.
Interventions
DRUGAvelumab
Given IV
BIOLOGICALIvuxolimab
Given IV
RADIATIONRadiation Therapy
Undergo radiation therapy
BIOLOGICALUtomilumab
Given IV
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must be refractory to, or intolerant of, established therapy known to provide clinical benefit for their conditions, or where subjects refuse existing therapies. * Subjects must have measurable disease (RECIST v 1.1) or patients may have bone metastatic disease evaluable by Prostate Cancer Working Group 2 (PCWG2) for subjects with metastatic castration-resistant prostate cancer (CRPC) or according to tumor evaluation criteria best suitable and accepted for the tumor type evaluated. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. * Platelets \>= 100 x 10\^9/L (For patients with hepatocellular carcinoma, platelets \>= 70 x 10\^9/L). * Hemoglobin \>= 9 g/dL. * Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L. * White blood cell (WBC) \>= 3 x 10\^9/L. * Alanine transaminase (ALT) =\< 2.5 x upper normal limit (ULN) (=\< 5 x ULN for subjects with documented metastatic disease to the liver). * Aspartate aminotransferase (AST) =\< 2.5 x ULN (=\< 5 x ULN for subjects with documented metastatic disease to the liver). * Alkaline phosphatase \< 4 x ULN. * Total bilirubin =\< 1.5 x ULN (In the expansion cohort, subjects with Gilbert's syndrome \[hereditary indirect hyperbilirubinemia\] who must have a total bilirubin of =\< 3 x ULN). * Albumin \>= 3 g/dL. * Serum creatinine =\< 2 x upper limit of normal (ULN) or estimated creatinine clearance \>= 30 ml/min as calculated using the Cockcroft-Gault formula. * Subject has recovered to grade =\< 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v 4.03) from the effects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or other targeted therapies, with the exception of alopecia. The exceptions for such effects are allowed lab values of =\< grade 2 specified elsewhere in these inclusion criteria. * Life expectancy of at least 12 weeks. * Negative serum pregnancy test in women of childbearing potential within 7 days of first dose of treatment and patients of child-bearing potential must agree to use effective contraception during and after 90 days post dose. A woman of childbearing potential is defined as a premenopausal female capable of becoming pregnant. This includes women on oral, injectable or mechanical contraception; women who are single and women whose male sexual partners have been vasectomized or whose male sexual partners have received or are utilizing mechanical contraceptive devices. * Subjects must have biopsiable disease. For Arms A, B, and C, subjects must have at least two lesions amenable to biopsy and response evaluation. For Arm D subjects should have at least three lesions amenable to biopsy, response evaluation, and radiation. Tumor lesions used for biopsy should not be lesions used as RECIST target lesions. However, if patients in Arm D do not have three separate lesions, patients will be eligible if there are two lesions, in which one is \> 2 centimeters (short axis) and can be used for both biopsy and response evaluation. * Subjects must give informed consent according to the rules and regulations of the individual participating sites.
Exclusion criteria
* Subjects with primary central nervous system (CNS) tumor or CNS tumor involvement. However, subjects with metastatic CNS tumors may participate in this study if the subject is: * \> 4 weeks from prior therapy completion (including radiation and/or surgery) * Clinically stable with respect to the CNS tumor at the time of study entry * Not receiving steroid therapy in treating CNS tumor or CNS tumor involvement * Not receiving anti-convulsive medications (that were started for brain metastases). * Major surgery, radiation therapy or systemic anti-cancer therapy within 4 weeks of study drug administration (6 weeks for mitomycin C or nitrosoureas). Palliative radiotherapy to a limited field is allowed after consultation with the medical monitor at any time during study participation, including during screening, unless it's clearly indicative of disease progression. * Subjects with prior anti-PD-1, anti-PD-L1 treatment. For Arms A and D, subjects may not have had prior 4-1BB treatment. For Arm B, subjects may not have had prior OX40 treatment. For Arm C, subjects may not have had prior 4-1BB or OX40 treatment. * Diagnosis or recurrence of invasive cancer other than the present cancer within 3 years (except basal or squamous cell carcinoma of the skin that has been definitively treated). * Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrollment), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (\>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication. * Active infection requiring systemic therapy. * Treatment with an investigational anti-cancer study drug within 4 weeks prior to study drug administration date. * Concurrent therapy with approved or investigational anticancer therapeutics. * Known prior severe hypersensitivity to investigational product(s) or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v 4.03 grade \>= 3). * Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. systemic corticosteroids at physiologic doses =\< 10 mg/day of prednisone or equivalent; c. steroids as premedication for hypersensitivity reactions (e.g., computed tomography \[CT\] scan premedication). * Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible. * Prior organ transplantation including allogenic stem-cell transplantation. * Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome. * Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test positive). * Vaccination (live attenuated virus) within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines. * Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade \> 1); however, alopecia, sensory neuropathy grade =\< 2, or other grade =\< 2 not constituting a safety risk based on investigator's judgment are acceptable. * Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study. * Medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results. * Pregnancy or lactation. * Men whose partner is a woman of child-bearing potential, (i.e. biologically able to conceive), and who is not employing two forms of highly effective contraception. Highly effective contraception (e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used by both sexes during the study and must be continued for 90 days after the end of study treatment. Women of child-bearing potential is defined as sexually mature women who are not surgically sterile or who have not been naturally postmenopausal for at least 12 consecutive months (e.g., who has had menses any time in the preceding 12 consecutive months). * A diagnosis of active scleroderma, lupus, or other rheumatologic disease which in the opinion of the treating radiation oncologist precludes safe radiation therapy. * Has had prior radiation therapy within the past 3 months where the high dose area of the prior radiation would overlap with the high dose area of the intended radiation based on the judgement of the treatment oncologist.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | DLT was assessed during the first 2 cycles or 8 weeks (56 days) since C1D1 of treatment. | DLTs were adverse events (AEs) related to study drug in the first 2 cycles and fulfilled one of the following * Discontinuation due to drug and/or XRT-related toxicity before DLT period ends * Delay \>28 days in receiving the next cycle due to drug and/or XRT-related toxicity * Hematologic * Gr4 neutropenia ≥7 days * Febrile neutropenia * Gr ≥3 thrombocytopenia associated with bleeding, or Gr 4 thrombocytopenia * Gr 4 anemia * Non-hematologic * Gr ≥3 nausea/vomiting or diarrhea ≥72 hours despite optimal supportive medications * Gr ≥3 fatigue ≥7 days * Gr≥2 pneumonitis ≥7 days despite corticosteroids * Gr≥3 rash ≥7 days despite treatment * Gr≥3 immune related toxicities ≥7 days despite corticosteroids * Any other Gr≥3 non-hematological toxicity (except for asymptomatic electrolytes abnormalities or hair loss which is not dose-limiting) * Gr≥3 AST, ALT, or total bilirubin elevation ≥7 days. Delay of treatment \> 14 days due to non-hematologic toxicity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate Per irRECIST | At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years. | Per Immune-related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST) using CT, MRI,or PET-CT scan: Immune-related Complete Response (irCR),Disappearance of all target lesions; Immune-related Partial Response (irPR), \>=30% decrease in the sum of the longest diameter of target and new lesions; OR = irCR + irPR. |
| Clinical Benefit Rate Per RECIST v1.1 | At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years. | Per RECIST v1.0 using CT, MRI,or PET-CT scan: CR,Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), Increase ≥20% of the sum of longest diameter compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion; Stable Disease (SD), Neither PR nor PD; Clinical benefit (CB) = CR + PR + SD ≥6 months. |
| Objective Response Rate Per RECIST v1.1 | At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years. | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) using CT, MRI,or PET-CT scan: Complete Response (CR),Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR. |
| Disease Control Rate Per RECIST v1.1 | At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years. | Per RECIST v1.0 using CT, MRI,or PET-CT scan: CR,Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; PD, Increase ≥20% of the sum of longest diameter compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion; SD, Neither PR nor PD; Disease control (DC) = CR + PR + SD. |
| Disease Control Rate Per irRECIST | At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years. | Per irRECIST using CT, MRI,or PET-CT scan: irCR,Disappearance of all target lesions; irPR, \>=30% decrease in the sum of the longest diameter of target and new lesions; irPD, Increase ≥20% of the sum of longest diameter of target and new lesion compared with nadir (minimum 5 mm) or progression of non-target lesions ; irSD, Neither irPR nor irPD; Disease control (DC) = irCR + irPR + irSD. |
| Clinical Benefit Rate Per irRECIST | At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years. | Per irRECIST using CT, MRI,or PET-CT scan: irCR,Disappearance of all target lesions; irPR, \>=30% decrease in the sum of the longest diameter of target and new lesions; Immune-related Progressive Disease (irPD), Increase ≥20% of the sum of longest diameter of target and new lesion compared with nadir (minimum 5 mm) or progression of non-target lesions ; Immune-related Stable Disease (irSD), Neither irPR nor irPD; Clinical benefit (CB) = irCR + irPR + irSD ≥6 months. |
Countries
United States
Participant flow
Recruitment details
This is an open label, single center Phase I/II combination study to evaluate safety, pharmacodynamics, and anti-tumor activity of avelumab in combination with other cancer immunotherapies in Pfizer pipeline with or without radiation (XRT), in patients within metastatic cancers at The University of Texas MD Anderson Cancer Center.
Pre-assignment details
Of the 173 patients enrolled, only 111 patients received at least 1 dose of the study agents. The remaining 62 patients screen failed and did not receive any dose of the study drugs. Per the protocol, all 111 patients who received one or more doses of drug were included in the analysis and the results are reported here.
Participants by arm
| Arm | Count |
|---|---|
| Arm A Exp Avelumab Starting From C1D15 Avelumab: 10 mg/kg IV every 2 weeks Utomilumab: 100 mg IV every 4 weeks | 16 |
| Arm A Exp Avelumab Starting From C3D1 Avelumab: 10 mg/kg IV every 2 weeks Utomilumab: 100 mg IV every 4 weeks | 8 |
| Arm B Exp Avelumab Starting From C1D15 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks Ivuxolimab: Given IV
Utomilumab: Given IV | 16 |
| Arm B Exp Avelumab Starting From C3D1 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks
Utomilumab: Given IV | 12 |
| Arm C Escalation Avelumab Starting From C1D1 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks Utomilumab: 20 mg IV every 4 weeks
Ivuxolimab: Given IV
Radiation Therapy: Undergo radiation therapy | 4 |
| Arm C Exp Avelumab Starting From C1D15 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks Utomilumab: 20 mg IV every 4 weeks
Avelumab: Given IV
Ivuxolimab: Given IV
Radiation Therapy: Undergo radiation therapy
Utomilumab: Given IV | 17 |
| Arm C Exp Avelumab Starting From C3D1 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks Utomilumab: 20 mg IV every 4 weeks | 11 |
| Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 Avelumab: 10 mg/kg IV every 2 weeks Utomilumab: 20 mg IV every 4 weeks XRT: 60 Gy for 10 fractions | 4 |
| Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 Avelumab: 10 mg/kg IV every 2 weeks Utomilumab: 20 mg IV every 4 weeks XRT: 60 Gy for 10 fractions | 3 |
| Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 Avelumab: 10 mg/kg IV every 2 weeks Utomilumab: 20 mg IV every 4 weeks XRT: 60 Gy for 10 fractions | 7 |
| Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks XRT: 60 Gy for 10 fractions | 3 |
| Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks XRT: 60 Gy for 10 fractions | 3 |
| Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks Utomilumab: 20 mg IV every 4 weeks XRT: 60 Gy for 10 fractions | 4 |
| Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 Avelumab: 10 mg/kg IV every 2 weeks Ivuxolimab: 0.3 mg/kg IV every 2 weeks Utomilumab: 20 mg IV every 4 weeks XRT: 60 Gy for 10 fractions | 3 |
| Total | 111 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 |
| Overall Study | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 12 | 6 | 15 | 11 | 3 | 14 | 10 | 4 | 2 | 7 | 3 | 1 | 3 | 1 |
| Overall Study | Removal of sole target lesion | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Stroke | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Toxicity and progression | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 | 1 | 1 | 2 | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 | Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 | Total | Arm A Exp Avelumab Starting From C3D1 | Arm B Exp Avelumab Starting From C1D15 | Arm B Exp Avelumab Starting From C3D1 | Arm C Escalation Avelumab Starting From C1D1 | Arm C Exp Avelumab Starting From C1D15 | Arm C Exp Avelumab Starting From C3D1 | Arm A Exp Avelumab Starting From C1D15 | Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 | Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 1 Participants | 0 Participants | 30 Participants | 1 Participants | 4 Participants | 5 Participants | 1 Participants | 6 Participants | 2 Participants | 5 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 3 Participants | 3 Participants | 81 Participants | 7 Participants | 12 Participants | 7 Participants | 3 Participants | 11 Participants | 9 Participants | 11 Participants | 4 Participants | 3 Participants | 5 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 12 Participants | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 3 Participants | 98 Participants | 7 Participants | 14 Participants | 10 Participants | 4 Participants | 15 Participants | 11 Participants | 14 Participants | 4 Participants | 2 Participants | 6 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 10 Participants | 0 Participants | 3 Participants | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 6 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 3 Participants | 87 Participants | 6 Participants | 12 Participants | 10 Participants | 2 Participants | 12 Participants | 9 Participants | 13 Participants | 4 Participants | 2 Participants | 7 Participants | 3 Participants |
| Region of Enrollment United States | 3 participants | 4 participants | 3 participants | 111 participants | 8 participants | 16 participants | 12 participants | 4 participants | 17 participants | 11 participants | 16 participants | 4 participants | 3 participants | 7 participants | 3 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants | 72 Participants | 8 Participants | 11 Participants | 11 Participants | 1 Participants | 12 Participants | 3 Participants | 9 Participants | 4 Participants | 2 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 2 Participants | 39 Participants | 0 Participants | 5 Participants | 1 Participants | 3 Participants | 5 Participants | 8 Participants | 7 Participants | 0 Participants | 1 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 16 | 6 / 8 | 13 / 16 | 10 / 12 | 3 / 4 | 15 / 17 | 9 / 11 | 4 / 4 | 3 / 3 | 7 / 7 | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 |
| other Total, other adverse events | 15 / 16 | 8 / 8 | 14 / 16 | 11 / 12 | 4 / 4 | 15 / 17 | 11 / 11 | 4 / 4 | 2 / 3 | 7 / 7 | 3 / 3 | 3 / 3 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 8 / 16 | 6 / 8 | 3 / 16 | 7 / 12 | 3 / 4 | 6 / 17 | 5 / 11 | 4 / 4 | 3 / 3 | 0 / 7 | 1 / 3 | 1 / 3 | 4 / 4 | 2 / 3 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria)
DLTs were adverse events (AEs) related to study drug in the first 2 cycles and fulfilled one of the following * Discontinuation due to drug and/or XRT-related toxicity before DLT period ends * Delay \>28 days in receiving the next cycle due to drug and/or XRT-related toxicity * Hematologic * Gr4 neutropenia ≥7 days * Febrile neutropenia * Gr ≥3 thrombocytopenia associated with bleeding, or Gr 4 thrombocytopenia * Gr 4 anemia * Non-hematologic * Gr ≥3 nausea/vomiting or diarrhea ≥72 hours despite optimal supportive medications * Gr ≥3 fatigue ≥7 days * Gr≥2 pneumonitis ≥7 days despite corticosteroids * Gr≥3 rash ≥7 days despite treatment * Gr≥3 immune related toxicities ≥7 days despite corticosteroids * Any other Gr≥3 non-hematological toxicity (except for asymptomatic electrolytes abnormalities or hair loss which is not dose-limiting) * Gr≥3 AST, ALT, or total bilirubin elevation ≥7 days. Delay of treatment \> 14 days due to non-hematologic toxicity
Time frame: DLT was assessed during the first 2 cycles or 8 weeks (56 days) since C1D1 of treatment.
Population: All enrolled patients who received at least one dose of each study medication in the assigned treatment combination were evaluable for DLT. Patients who missed any doses during the DLT period for reasons unrelated to study drug and patients who are lost to follow-up due to reasons unrelated to treatment related AEs are not evaluable for DLT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A Exp Avelumab Starting From C1D15 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm A Exp Avelumab Starting From C3D1 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm B Exp Avelumab Starting From C1D15 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm B Exp Avelumab Starting From C3D1 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm C Escalation Avelumab Starting From C1D1 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm C Exp Avelumab Starting From C1D15 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm C Exp Avelumab Starting From C3D1 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
| Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 2 Participants |
| Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 | Number of Participants With Dose-limiting Toxicities (DLTs) (All Will be Graded According to CTCAEv4.03 Criteria) | 0 Participants |
Secondary
Clinical Benefit Rate Per irRECIST
Per irRECIST using CT, MRI,or PET-CT scan: irCR,Disappearance of all target lesions; irPR, \>=30% decrease in the sum of the longest diameter of target and new lesions; Immune-related Progressive Disease (irPD), Increase ≥20% of the sum of longest diameter of target and new lesion compared with nadir (minimum 5 mm) or progression of non-target lesions ; Immune-related Stable Disease (irSD), Neither irPR nor irPD; Clinical benefit (CB) = irCR + irPR + irSD ≥6 months.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Population: All enrolled patients who were eligible, had received at least one cycle of therapy, and had baseline assessments and at least 1 on-study tumor assessment were considered evaluable for response. Patients who were treated and removed from study prior to on-study tumor assessment because of disease progression were also considered evaluable . In XRT arms, patients were considered evaluable on the study if patients received 75% of radiation dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A Exp Avelumab Starting From C1D15 | Clinical Benefit Rate Per irRECIST | 1 Participants |
| Arm A Exp Avelumab Starting From C3D1 | Clinical Benefit Rate Per irRECIST | 3 Participants |
| Arm B Exp Avelumab Starting From C1D15 | Clinical Benefit Rate Per irRECIST | 0 Participants |
| Arm B Exp Avelumab Starting From C3D1 | Clinical Benefit Rate Per irRECIST | 1 Participants |
| Arm C Escalation Avelumab Starting From C1D1 | Clinical Benefit Rate Per irRECIST | 0 Participants |
| Arm C Exp Avelumab Starting From C1D15 | Clinical Benefit Rate Per irRECIST | 0 Participants |
| Arm C Exp Avelumab Starting From C3D1 | Clinical Benefit Rate Per irRECIST | 1 Participants |
| Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Clinical Benefit Rate Per irRECIST | 0 Participants |
| Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Clinical Benefit Rate Per irRECIST | 0 Participants |
| Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 | Clinical Benefit Rate Per irRECIST | 1 Participants |
| Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Clinical Benefit Rate Per irRECIST | 0 Participants |
| Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Clinical Benefit Rate Per irRECIST | 0 Participants |
| Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 | Clinical Benefit Rate Per irRECIST | 0 Participants |
| Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 | Clinical Benefit Rate Per irRECIST | 0 Participants |
Secondary
Clinical Benefit Rate Per RECIST v1.1
Per RECIST v1.0 using CT, MRI,or PET-CT scan: CR,Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), Increase ≥20% of the sum of longest diameter compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion; Stable Disease (SD), Neither PR nor PD; Clinical benefit (CB) = CR + PR + SD ≥6 months.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Population: All enrolled patients who were eligible, had received at least one cycle of therapy, and had baseline assessments and at least 1 on-study tumor assessment were considered evaluable for response. Patients who were treated and removed from study prior to on-study tumor assessment because of disease progression were also considered evaluable. In XRT arms, patients were considered evaluable on the study if patients received 75% of radiation dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A Exp Avelumab Starting From C1D15 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm A Exp Avelumab Starting From C3D1 | Clinical Benefit Rate Per RECIST v1.1 | 3 Participants |
| Arm B Exp Avelumab Starting From C1D15 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm B Exp Avelumab Starting From C3D1 | Clinical Benefit Rate Per RECIST v1.1 | 1 Participants |
| Arm C Escalation Avelumab Starting From C1D1 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm C Exp Avelumab Starting From C1D15 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm C Exp Avelumab Starting From C3D1 | Clinical Benefit Rate Per RECIST v1.1 | 1 Participants |
| Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
| Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 | Clinical Benefit Rate Per RECIST v1.1 | 0 Participants |
Secondary
Disease Control Rate Per irRECIST
Per irRECIST using CT, MRI,or PET-CT scan: irCR,Disappearance of all target lesions; irPR, \>=30% decrease in the sum of the longest diameter of target and new lesions; irPD, Increase ≥20% of the sum of longest diameter of target and new lesion compared with nadir (minimum 5 mm) or progression of non-target lesions ; irSD, Neither irPR nor irPD; Disease control (DC) = irCR + irPR + irSD.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Population: All enrolled patients who were eligible, had received at least one cycle of therapy, and had baseline assessments and at least 1 on-study tumor assessment were considered evaluable for response. Patients who were treated and removed from study prior to on-study tumor assessment because of disease progression were also considered evaluable. In XRT arms, patients were considered evaluable on the study if patients received 75% of radiation dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A Exp Avelumab Starting From C1D15 | Disease Control Rate Per irRECIST | 7 Participants |
| Arm A Exp Avelumab Starting From C3D1 | Disease Control Rate Per irRECIST | 6 Participants |
| Arm B Exp Avelumab Starting From C1D15 | Disease Control Rate Per irRECIST | 5 Participants |
| Arm B Exp Avelumab Starting From C3D1 | Disease Control Rate Per irRECIST | 5 Participants |
| Arm C Escalation Avelumab Starting From C1D1 | Disease Control Rate Per irRECIST | 1 Participants |
| Arm C Exp Avelumab Starting From C1D15 | Disease Control Rate Per irRECIST | 5 Participants |
| Arm C Exp Avelumab Starting From C3D1 | Disease Control Rate Per irRECIST | 5 Participants |
| Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Disease Control Rate Per irRECIST | 2 Participants |
| Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Disease Control Rate Per irRECIST | 0 Participants |
| Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 | Disease Control Rate Per irRECIST | 2 Participants |
| Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Disease Control Rate Per irRECIST | 1 Participants |
| Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Disease Control Rate Per irRECIST | 2 Participants |
| Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 | Disease Control Rate Per irRECIST | 2 Participants |
| Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 | Disease Control Rate Per irRECIST | 0 Participants |
Secondary
Disease Control Rate Per RECIST v1.1
Per RECIST v1.0 using CT, MRI,or PET-CT scan: CR,Disappearance of all target lesions; PR, \>=30% decrease in the sum of the longest diameter of target lesions; PD, Increase ≥20% of the sum of longest diameter compared with nadir (minimum 5 mm) or progression of non-target lesions or new lesion; SD, Neither PR nor PD; Disease control (DC) = CR + PR + SD.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Population: All enrolled patients who were eligible, had received at least one cycle of therapy, and had baseline assessments and at least 1 on-study tumor assessment were considered evaluable for response. Patients who were treated and removed from study prior to on-study tumor assessment because of disease progression were also considered evaluable . In XRT arms, patients were considered evaluable on the study if patients received 75% of radiation dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A Exp Avelumab Starting From C1D15 | Disease Control Rate Per RECIST v1.1 | 4 Participants |
| Arm A Exp Avelumab Starting From C3D1 | Disease Control Rate Per RECIST v1.1 | 7 Participants |
| Arm B Exp Avelumab Starting From C1D15 | Disease Control Rate Per RECIST v1.1 | 2 Participants |
| Arm B Exp Avelumab Starting From C3D1 | Disease Control Rate Per RECIST v1.1 | 5 Participants |
| Arm C Escalation Avelumab Starting From C1D1 | Disease Control Rate Per RECIST v1.1 | 1 Participants |
| Arm C Exp Avelumab Starting From C1D15 | Disease Control Rate Per RECIST v1.1 | 4 Participants |
| Arm C Exp Avelumab Starting From C3D1 | Disease Control Rate Per RECIST v1.1 | 5 Participants |
| Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Disease Control Rate Per RECIST v1.1 | 2 Participants |
| Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Disease Control Rate Per RECIST v1.1 | 0 Participants |
| Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 | Disease Control Rate Per RECIST v1.1 | 1 Participants |
| Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Disease Control Rate Per RECIST v1.1 | 1 Participants |
| Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Disease Control Rate Per RECIST v1.1 | 2 Participants |
| Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 | Disease Control Rate Per RECIST v1.1 | 2 Participants |
| Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 | Disease Control Rate Per RECIST v1.1 | 0 Participants |
Secondary
Objective Response Rate Per irRECIST
Per Immune-related Response Evaluation Criteria In Solid Tumors Criteria (irRECIST) using CT, MRI,or PET-CT scan: Immune-related Complete Response (irCR),Disappearance of all target lesions; Immune-related Partial Response (irPR), \>=30% decrease in the sum of the longest diameter of target and new lesions; OR = irCR + irPR.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Population: All enrolled patients who were eligible, had received at least one cycle of therapy, and had baseline assessments and at least 1 on-study tumor assessment were considered evaluable for response. Patients who were treated and removed from study prior to on-study tumor assessment because of disease progression were also considered evaluable. In XRT arms, patients were considered evaluable on the study if patients received 75% of radiation dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A Exp Avelumab Starting From C1D15 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm A Exp Avelumab Starting From C3D1 | Objective Response Rate Per irRECIST | 1 Participants |
| Arm B Exp Avelumab Starting From C1D15 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm B Exp Avelumab Starting From C3D1 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm C Escalation Avelumab Starting From C1D1 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm C Exp Avelumab Starting From C1D15 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm C Exp Avelumab Starting From C3D1 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 | Objective Response Rate Per irRECIST | 1 Participants |
| Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 | Objective Response Rate Per irRECIST | 0 Participants |
| Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 | Objective Response Rate Per irRECIST | 0 Participants |
Secondary
Objective Response Rate Per RECIST v1.1
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) using CT, MRI,or PET-CT scan: Complete Response (CR),Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Objective Response (OR) = CR + PR.
Time frame: At baseline and at 8-week intervals (± 7 days). Confirmatory scans were obtained 4-8 weeks following initial objective response. After 1 year of treatment scans at 12-week intervals (± 7 days), independent of cycle delays, assessed upto 3 years.
Population: All enrolled patients who were eligible, had received at least one cycle of therapy, and had baseline assessments and at least 1 on-study tumor assessment were considered evaluable for response. Patients who were treated and removed from study prior to on-study tumor assessment because of disease progression were also considered evaluable. In XRT arms, patients were considered evaluable on the study if patients received 75% of radiation dose
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A Exp Avelumab Starting From C1D15 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm A Exp Avelumab Starting From C3D1 | Objective Response Rate Per RECIST v1.1 | 1 Participants |
| Arm B Exp Avelumab Starting From C1D15 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm B Exp Avelumab Starting From C3D1 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm C Escalation Avelumab Starting From C1D1 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm C Exp Avelumab Starting From C1D15 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm C Exp Avelumab Starting From C3D1 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm D Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm D Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm D Esc Schedule-3 Dose Level 1; XRT: Starting C1D1 to C1D3 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm E Esc Schedule-1 Dose Level 1; XRT: Starting C1D2 to C1D11 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm E Esc Schedule-2 Dose Level 1; XRT: Starting Days -14 to -1 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm F Esc Schedule-1 Dose Level 1; Avelumab Starting From C1D1, XRT: Starting C1D2 to C1D11 | Objective Response Rate Per RECIST v1.1 | 0 Participants |
| Arm F Esc Schedule-2 Dose Level 1; Avelumab Starting From C1D15, XRT: Starting Days -14 to -1 | Objective Response Rate Per RECIST v1.1 | 0 Participants |