Carcinoma, Unspecified Site
Conditions
Brief summary
Single-arm phase 2 study to examine pembrolizumab and concurrent radiation to induce an abscopal effect in patients with previously treated carcinoma of unknown primary (CUP16-268)
Detailed description
This is a proof-of-principle single-arm phase 2 study in patients with previously treated CUP. All patients receive pembrolizumab combined with Radiation Therapy (RT) to a metastatic site, so as to induce an abscopal tumor response. The treatment combination will be repeated with RT delivery to a second metastatic site in a non-overlapping RT field. The results will be compared with historical control. The primary endpoint is the confirmed response rate (RR) in a non-irradiated site based on best responding abscopal lesion. This study will also evaluate the following secondary endpoints: RR in a non-irradiated site based on RECIST 1.1, adverse events, progression-free survival (PFS), overall survival (OS), time-to-progression (TTP), and disease control rate (DCR).
Interventions
DRUGPembrolizumab
200mg IV at day -21, then day 1 of each 21-day cycle for a maximum of 24 continuous months of Pembrolizumab (35 cycles) from Cycle 1 Day 1 (C1D1) can be administered.
RADIATIONExternal Beam Radiation Therapy
20-30 Gy over five fractions for up to two cycles.
Sponsors
Merck Sharp & Dohme LLC
Hoosier Cancer Research Network
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. * Age ≥ 18 years at the time of consent. * Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2 within 28 days prior to registration. * Archival tissue must be available and identified during screening and shipped prior to Day -21. If archival tissue is not available and the subject is not undergoing a standard of care biopsy, the subject must undergo a research biopsy to obtain fresh tissue prior to start of treatment. * Carcinoma of unknown primary after the following diagnostic procedures have been performed if clinically indicated and are unrevealing of the primary site: * Complete history and clinically appropriate physical * CT scan of chest, abdomen, and pelvis * Directed evaluation of symptomatic areas * Mammogram in women * Colonoscopy in patients with liver metastasis or an elevated CEA * Direct pathologic comparison with prior tumor specimens, where possible, even if prior tumor is early-stage or clinically remote from current disease NOTE: Immunohistochemical stains will be performed according to institutional standards. If a primary carcinoma is identified, the patient should undergo treatment as appropriate for that primary tumor and not be enrolled in the study. The above diagnostic workup does not need to be performed if: (1) it was previously completed at the time of original diagnosis or (2) the investigator does not believe the workup has clinical utility at the current time, given that the patient has received interval therapy. * Histologic confirmation of metastatic adenocarcinoma, poorly differentiated non-small cell carcinoma, or poorly differentiated squamous carcinoma. NOTE: Pathology consultation at Mayo Clinic is recommended if clinically indicated. One scenario is where unknown primary is the most likely diagnosis but immunostains show relatively site-specific marker staining (e.g., CD45, TTF1, chromogranin, GATA3, PAX8, PSA, melanocytic markers). Information provided for pathology consultation should include recent H&P and imaging reports. * If and when available, submission of genomic sequencing and expression profiling results is mandatory. Results of testing are not required prior to treatment. * At least one measurable lesion (per RECIST 1.1) outside the planned RT fields. * Stable or progressive disease after, or was unable to tolerate, at least one line of prior anticancer therapy for this disease. NOTE: For patients with stable disease, it is strongly encouraged to confirm the presence of active disease (eg, demonstrating 18F-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG) avidity via PET or repeat biopsy). * Radiation oncology consultation at enrolling site ≤ 56 days prior to registration to confirm at least two metastatic lesions which are targetable by RT at doses and schedule prescribed in this study and which reside in non-overlapping RT fields. * Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to registration. * Hematological * Absolute Neutrophil Count (ANC) ≥ 900 K/mm3 * Hemoglobin (Hgb) ≥ 8.5 g/dL without transfusion or EPO dependency (≤ 7 days prior to assessment) * Platelets ≥ 90,000 / mcL * Renal ---Creatinine OR Calculated creatinine clearance: ≤ 1.5 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN * Hepatic * Bilirubin Total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN OR total bilirubin ≤2 X ULN if liver metastases are present * Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases * Albumin \> 2.5 g/dL * Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to registration. NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: breast milk cannot be stored for future use while the mother is being treated on study * Females of childbearing potential and males must be willing to abstain from heterosexual activity (abstinence) or use effective methods of contraception as described in the protocol from the time of informed consent until 120 days after treatment discontinuation. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months * Willingness to return to the enrolling institution for follow up * Willingness to provide tissue and blood samples for correlative research purposes
Exclusion criteria
* Prior radiation to an area of the body which, if included in the current radiation field, poses an unacceptably high risk of toxicity in the opinion of the investigator. NOTE: A prior field that overlaps with the current field, by itself, does not exclude the patient. * Any of the following --Melanoma. NOTE: Positive tumor staining for S-100 or HMB45 alone does not exclude patients. ---If immunostains are performed, and any of the below tests are positive: * Hematologic CD45+ (others such as CD2, CD20, CD30, CD43 also suggest hematologic origin) * Lung or thyroid origin (Thyroid Transcription Factor \[TTF-1\]). NOTE: Patients with biopsy proven TTF-1 positive tumor who do not have clinical evidence for either lung or thyroid cancer (e.g. a dominant lung mass) are still eligible. * Progressed on 4 or more lines of prior chemotherapy for this cancer. NOTE: Bisphosphonates and neoadjuvant/adjuvant anticancer therapies (including locally directed therapies) do not count as a line of therapy with regard to this
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Abscopal Response Rate | From Cycle 3, Day 1 (each cycle is 21 days) (C3D1) until death or up to a maximum of 19 months | Evaluate the abscopal response rate in Carcinoma of Unknown Primary (CUP) patients treated with the combination of pembrolizumab plus radiotherapy. Best abscopal response is defined as the frequency of patients whose best responding abscopal lesion demonstrates at least a 30% decrease in its longest diameter from baseline (Golden et al., 2015). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate Treatment-related Toxicity. | From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 9 months | The maximum grade for each type of adverse event will be summarized using CTCAE version 4.0 criteria. The frequency and percentage of grade 2+ adverse events will be summarized using CTCAE version 4.0 criteria. |
| Progression-Free Survival | From Cycle 1, Day 1 (each cycle is 21 days) until progression or death or up to a maximum of 6 months | Progression-free survival (PFS) is defined as the time from registration to the first of either disease progression or death from any cause, where disease progression will be determined based on RECIST 1.1 criteria. Patients that are alive and progression-free will be censored on their last tumor evaluation date. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Overall Survival | From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 19 months | Overall Survival (OS) is defined as the time from registration to death from any cause. Subjects who did not die will be censored at their last visit. |
| Response Rate | From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 19 months | To determine the response rate by RECIST 1.1 and informed by irRECIST, of non-irradiated metastatic sites when pembrolizumab is combined with radiotherapy. Subjects with confirmed CR or PR per RECIST 1.1 should be considered. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Disease Control Rate | From Cycle 1, Day 1 (each cycle is 21 days) to a maximum of 19 months | Disease Control Rate (DCR) is defined as the frequency (%) of patients who have a best response of PR, CR, or Stable disease based on RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum of the longest diameter since the treatment started. |
| Explore the Association Between Response Rate (RR) and Other Endpoints (e.g., OS, PFS) | From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 19 months | The association between RR (using RECIST 1.1 (informed by irRECIST)) with other clinical endpoints (e.g., OS, PFS, etc.) was performed. |
| Time-to-Progression | From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 6 months | Time-to-Progression (TTP) is defined as the time from registration to disease progression, where patients that are progression-free will be censored on their last tumor evaluation date. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A : Pembrolizumab + External Beam Radiation Therapy Pembrolizumab + External Beam Radiation Therapy
Pembrolizumab: 200mg IV at day -21, then day 1 of each 21-day cycle for a maximum of 24 continuous months of Pembrolizumab (35 cycles) from C1D1 can be administered.
External Beam Radiation Therapy: 20-30 Gy over five fractions for up to two cycles. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Follow up - Up to 2 Years | Death | 9 |
| Follow up - Up to 2 Years | Patient lost to follow up | 1 |
| Follow up - Up to 2 Years | Patient Refused to follow up | 1 |
| Follow up - Up to 2 Years | Patient stopped protocol treatment due to lack of response to treatment regimen. | 1 |
| Follow up - Up to 2 Years | Patient would like to seek treatments locally. | 1 |
| Follow up - Up to 2 Years | study terminated | 1 |
| Study Treatment - Up to 22 Months | AE / Side Effects / Complications | 3 |
| Study Treatment - Up to 22 Months | Alternative Cancer Therapy | 2 |
| Study Treatment - Up to 22 Months | Death | 2 |
| Study Treatment - Up to 22 Months | Disease Progression | 6 |
| Study Treatment - Up to 22 Months | Symptomatic Deterioration | 1 |
Baseline characteristics
| Characteristic | Arm A : Pembrolizumab + External Beam Radiation Therapy |
|---|---|
| Abdominal/Pelvic involvement No | 1 Participants |
| Abdominal/Pelvic involvement Yes | 13 Participants |
| Age, Continuous | 55.0 years |
| Bone involvement No | 9 Participants |
| Bone involvement Yes | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Histology Adenocarcinoma | 6 Participants |
| Histology Carcinoma, NOS | 4 Participants |
| Histology Squamous Carcinoma | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 8 Participants |
| Thoracic involvement No | 5 Participants |
| Thoracic involvement Yes | 9 Participants |
| Total number of metastatic sites | 3 number of sites |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 9 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 7 / 14 |
Outcome results
Primary
Abscopal Response Rate
Evaluate the abscopal response rate in Carcinoma of Unknown Primary (CUP) patients treated with the combination of pembrolizumab plus radiotherapy. Best abscopal response is defined as the frequency of patients whose best responding abscopal lesion demonstrates at least a 30% decrease in its longest diameter from baseline (Golden et al., 2015).
Time frame: From Cycle 3, Day 1 (each cycle is 21 days) (C3D1) until death or up to a maximum of 19 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Abscopal Response Rate | 7.1 percentage of participants |
Secondary
Disease Control Rate
Disease Control Rate (DCR) is defined as the frequency (%) of patients who have a best response of PR, CR, or Stable disease based on RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; stable disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD), taking as reference the smallest sum of the longest diameter since the treatment started.
Time frame: From Cycle 1, Day 1 (each cycle is 21 days) to a maximum of 19 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Disease Control Rate | 35.7 percentage of participants |
Secondary
Evaluate Treatment-related Toxicity.
The maximum grade for each type of adverse event will be summarized using CTCAE version 4.0 criteria. The frequency and percentage of grade 2+ adverse events will be summarized using CTCAE version 4.0 criteria.
Time frame: From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 9 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Evaluate Treatment-related Toxicity. | Number of patients had at least one adverse event of any grade | 14 Participants |
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Evaluate Treatment-related Toxicity. | Number of patients had at least one grade 3 or greater adverse event | 8 Participants |
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Evaluate Treatment-related Toxicity. | Number of patients had at least one grade 3 or greater treatment related adverse event | 5 Participants |
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Evaluate Treatment-related Toxicity. | Number of patients having serious adverse event | 7 Participants |
Secondary
Explore the Association Between Response Rate (RR) and Other Endpoints (e.g., OS, PFS)
The association between RR (using RECIST 1.1 (informed by irRECIST)) with other clinical endpoints (e.g., OS, PFS, etc.) was performed.
Time frame: From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 19 months
Population: Per RECIST 1.1 criteria, no confirmed CR or PR responses were observed.
Secondary
Overall Survival
Overall Survival (OS) is defined as the time from registration to death from any cause. Subjects who did not die will be censored at their last visit.
Time frame: From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 19 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Overall Survival | 8.2 months |
Secondary
Progression-Free Survival
Progression-free survival (PFS) is defined as the time from registration to the first of either disease progression or death from any cause, where disease progression will be determined based on RECIST 1.1 criteria. Patients that are alive and progression-free will be censored on their last tumor evaluation date. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From Cycle 1, Day 1 (each cycle is 21 days) until progression or death or up to a maximum of 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Progression-Free Survival | 2.2 months |
Secondary
Response Rate
To determine the response rate by RECIST 1.1 and informed by irRECIST, of non-irradiated metastatic sites when pembrolizumab is combined with radiotherapy. Subjects with confirmed CR or PR per RECIST 1.1 should be considered. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 19 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Response Rate | 0 Participants |
Secondary
Time-to-Progression
Time-to-Progression (TTP) is defined as the time from registration to disease progression, where patients that are progression-free will be censored on their last tumor evaluation date.
Time frame: From Cycle 1, Day 1 (each cycle is 21 days) until death or up to a maximum of 6 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A : Pembrolizumab + External Beam Radiation Therapy | Time-to-Progression | 3.5 months |