Cancer of Unknown Primary Site
Conditions
Brief summary
This study will compare the efficacy and safety of molecularly-guided therapy versus standard platinum-containing chemotherapy in participants with poor-prognosis cancer of unknown primary site (CUP; non-specific subset) who have achieved disease control after 3 cycles of first-line platinum based induction chemotherapy.
Interventions
DRUGAlectinib
Alectinib will be administered orally at the label-recommended dose (600 mg) twice daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
DRUGVismodegib
Vismodegib will be administered orally at the label-recommended dose (150 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
DRUGIpatasertib
Ipatasertib will be administered orally at the label-recommended dose (400 mg) once daily on Days 1-21 of each 28-day Cycle in combination with paclitaxel, and as monotherapy after the final administration of paclitaxel, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
DRUGOlaparib
Olaparib will be administered orally at the label-recommended dose (400 mg) twice daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
DRUGErlotinib
Erlotinib will be administered orally in combination with Bevacizumab at the label recommended dose (150 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
DRUGBevacizumab
Bevacizumab will be administered intravenously at 15mg/kg every 3 weeks in combination with Erlotinib until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
DRUGVemurafenib
Vemurafenib will be administered orally, 960 mg twice daily, in combination with Cobimetinib, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
DRUGCobimetinib
Cobimetinib will be administered orally, 60mg once daily, in combination with Vemurafenib, on Days 1-21 of each 28-day Cycle, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
DRUGTrastuzumab Subcutaneous (SC)
Trastuzumab will be administered subcutaneously, 600 mg every 3 weeks, in combination with Pertuzumab and chemotherapy, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
DRUGPertuzumab
Pertuzumab will be initially be administered intravenously, 840 mg, followed by 420 mg every 3 weeks, in combination with Trastuzumab and chemotherapy, until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months)
DRUGAtezolizumab
Atezolizumab will be administered intravenously at the label-recommended dose (1200 mg), alone or in combination with chemotherapy, every 3 weeks until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
DRUGCarboplatin
Carboplatin will be administered intravenously at the area under the curve (AUC) dose once every 3 weeks for up to 9 Cycles (Cycle = 21 days) in some combination with the following: Paclitaxel, Gemcitabine, Atezolizumab, Pertuzumab, and Trastuzumab SC.
DRUGPaclitaxel
Paclitaxel will be administered intravenously, 175 mg/m\^2, once every 3 weeks for up to 9 cycles (Cycle = 21 days) in some combination with the following: Carboplatin, Ipatasertib, Atezolizumab, Pertuzumab, and Trastuzumab SC
DRUGCisplatin
Cisplatin will be administered intravenously, 60-75 mg/m\^2, once every three weeks, for up to 9 cycles (Cycle = 21 days) in some combination with the following: Gemcitabine, Paclitaxel, Atezolizumab, Pertuzumab, and Trastuzumab SC.
DRUGGemcitabine
Gemcitabine will be administered intravenously, 1000 mg/m\^2, twice every three weeks for up to 9 cycles (Cycle = 21 days) in some combination with the following: Cisplatin, Carboplatin, Atezolizumab, Pertuzumab, and Trastuzumab SC.
DRUGEntrectinib
Entrectinib will be administered orally at the label-recommended dose (600 mg) once daily until loss of clinical benefit or unacceptable toxicity, through the end of the study (approximately 70 months).
DRUGIvosidenib
Ivosidenib will be administered orally at the label-recommended dose (500mg) once daily across a 28-day treatment cycle until loss of clinical benefit or unacceptable toxicity.
DRUGPemigatinib
Pemigatinib will be administered orally at the label-recommended dose (13.5mg) once daily across a 21-day treatment cycle until loss of clinical benefit or unacceptable toxicity.
Sponsors
Foundation Medicine
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically-confirmed unresectable cancer of unknown primary site (CUP) diagnosed according to criteria defined in the 2015 European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for CUP * No prior lines of systemic therapy for the treatment of CUP * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Candidate for platinum-based chemotherapy (according to the reference information for the intended chemotherapy) * At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) * Formalin-Fixed Paraffin-Embedded (FFPE) tumor tissue sample \</= 4 months old that is expected to be sufficient for generation of a comprehensive genomic profile at a central reference pathology laboratory
Exclusion criteria
* Squamous cell CUP * Participants who can be assigned to a specific subset of CUP for which a specific treatment is recommended by the 2015 ESMO Clinical Practice Guidelines for CUP or with a clinical and IHC profile indicative of a specific primary tumor (favorable prognosis CUP subsets): Poorly differentiated carcinoma with midline distribution; women with papillary adenocarcinoma of the peritoneal cavity; women with adenocarcinoma involving only the axillary lymph nodes; squamous cell carcinoma of the cervical lymph nodes; poorly differentiated neuroendocrine tumors; men with blastic bone metastases and elevated prostate-specific antigen (PSA); participants with a single, small, potentially resectable tumor; colon cancer-type CUP, including participants with a CK7 negative, CK20 positive, CDX-2 positive immunohistochemistry profile; CK7-positive, CK20-negative and TTF-1 positive tumors in a context suggestive of lung adenocarcinoma or thyroid cancer; IHC profile definitely indicative of breast cancer OR an IHC profile indicative of breast cancer and either a history of breast cancer or lymph nodes in the drainage areas of the breast; high-grade serious carcinoma histology and elevated CA125 tumor marker and/or a mass in the gynecological tract or any tumor mass or lymph node in the abdominal cavity; IHC profile suggestive of renal cell carcinoma and renal lesions, with a Bosniak classification higher than IIF; IHC profile compatible with cholangiocarcinoma or pancreatobiliary (or upper gastrointestinal carcinoma) AND 1 or 2 liver lesions without extrahepatic disease or with only pulmonary metastases and/or lymph nodes in the drainage areas of the liver * Known presence of brain or spinal cord metastasis (including metastases that have been irradiated only) * Histology and immunohistology profiles (per 2015 ESMO guidelines) that are not adenocarcinoma or poorly differentiated carcinoma/adenocarcinoma * History or known presence of leptomeningeal disease * Known human immunodeficiency virus (HIV) infection * Significant cardiovascular disease * Prior allogeneic stem cell or solid organ transplantation * Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or for up to 7 months after the final dose of treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | From randomization to the first occurrence of disease progression or death from any cause, until 330 PFS events were observed (approx. 4.3 years for MGT Cat 1 and 3.4 years for Chemotherapy Cat 1). | This efficacy objective was to evaluate the efficacy of MGT vs platinum chemotherapy in term of PFS in participants with CUP whose best response to 3 cycles of platinum induction chemotherapy was assessed CR, PR, or SD. |
Secondary
| Measure | Time frame |
|---|---|
| Overall Survival (OS) | From randomization to death from any cause (approx. 4 years) |
| Objective Response Rate (ORR) | Two consecutive occurrences of complete or partial response >/=4 weeks apart (up to approximately 4 months) |
| Duration of Response (DOR) | From the first documentation of a complete response (CR) or partial response (PR) to disease progression or death from any cause, whichever occurs first (up to approximately 4 years) |
| Disease Control Rate (DCR) | From randomization to death from any cause, through the end of study (approximately 4 years) |
Countries
Australia, Austria, Brazil, Bulgaria, Chile, Colombia, Croatia, Czechia, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Israel, Italy, Japan, Latvia, Mexico, Netherlands, Norway, Peru, Poland, Portugal, Romania, South Korea, Spain, Switzerland, Thailand, Turkey (Türkiye), United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Molecularly-Guided Therapy (MGT) Category 1 Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study). MGT was chosen based on each participant's comprehensive genomic profile and administered until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first. | 326 |
| Chemotherapy Category 1 Category 1 included participants with cancer of unknown primary site (CUP) with a complete response (CR), partial response (PR), or stable disease (SD) after 3 cycles of platinum induction chemotherapy (provided at the beginning of the study).
Participants in this arm continued to receive the same chemotherapy regimen used during induction for a minimum of 3 additional cycles. | 110 |
| Category 2 Category 2 included participants with progressive disease (PD) after 3 cycles of platinum induction chemotherapy. Participants in this arm received either MGT based on their comprehensive genomic profile until loss of clinical benefit, unacceptable toxicity, participant or investigator decision to discontinue, or death, whichever occurred first, or the same chemotherapy regimen used during induction for a minimum of 3 additional cycles. | 93 |
| Total | 529 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 227 | 79 | 84 |
| Overall Study | Exclusion criteria | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 4 | 3 | 3 |
| Overall Study | No profile due to technical failure | 1 | 0 | 0 |
| Overall Study | Physician Decision | 3 | 1 | 0 |
| Overall Study | Study terminated by sponsor | 79 | 21 | 4 |
| Overall Study | Withdrawal by Subject | 11 | 6 | 2 |
Baseline characteristics
| Characteristic | Total | Category 2 | Chemotherapy Category 1 | Molecularly-Guided Therapy (MGT) Category 1 |
|---|---|---|---|---|
| Age, Continuous | 60.42 Years STANDARD_DEVIATION 11.62 | 59.2 Years STANDARD_DEVIATION 12.7 | 61.1 Years STANDARD_DEVIATION 11.3 | 60.5 Years STANDARD_DEVIATION 11.5 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 8 Participants | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 50 Participants | 7 Participants | 12 Participants | 31 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 0 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 35 Participants | 4 Participants | 9 Participants | 22 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 413 Participants | 76 Participants | 85 Participants | 252 Participants |
| Race/Ethnicity, Customized Not Stated | 49 Participants | 7 Participants | 11 Participants | 31 Participants |
| Race/Ethnicity, Customized Unknown | 72 Participants | 15 Participants | 14 Participants | 43 Participants |
| Race/Ethnicity, Customized White | 393 Participants | 70 Participants | 81 Participants | 242 Participants |
| Sex: Female, Male Female | 258 Participants | 44 Participants | 53 Participants | 161 Participants |
| Sex: Female, Male Male | 271 Participants | 49 Participants | 57 Participants | 165 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 227 / 326 | 79 / 110 | 84 / 93 |
| other Total, other adverse events | 279 / 312 | 81 / 102 | 73 / 93 |
| serious Total, serious adverse events | 119 / 312 | 15 / 102 | 39 / 93 |
Outcome results
Primary
Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1)
This efficacy objective was to evaluate the efficacy of MGT vs platinum chemotherapy in term of PFS in participants with CUP whose best response to 3 cycles of platinum induction chemotherapy was assessed CR, PR, or SD.
Time frame: From randomization to the first occurrence of disease progression or death from any cause, until 330 PFS events were observed (approx. 4.3 years for MGT Cat 1 and 3.4 years for Chemotherapy Cat 1).
Population: The intent-to-treat (ITT) population included all Category 1 randomized participants, whether or not the assigned study treatment was received. Endpoints for Category 2 were exploratory and were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Molecularly-Guided Therapy (MGT) Category 1 | Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | 6.14 Months |
| Chemotherapy Category 1 | Progression Free Survival (PFS) as Assessed by the Investigator According to Response Evaluation Criteria In Solid Tumors v1.1 (RECIST v1.1) | 4.40 Months |
p-value: 0.017795% CI: [0.59, 0.95]Stratified log-rank
Secondary
Disease Control Rate (DCR)
Time frame: From randomization to death from any cause, through the end of study (approximately 4 years)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molecularly-Guided Therapy (MGT) Category 1 | Disease Control Rate (DCR) | 64.7 Percentage of responders |
| Chemotherapy Category 1 | Disease Control Rate (DCR) | 60.0 Percentage of responders |
Secondary
Duration of Response (DOR)
Time frame: From the first documentation of a complete response (CR) or partial response (PR) to disease progression or death from any cause, whichever occurs first (up to approximately 4 years)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Molecularly-Guided Therapy (MGT) Category 1 | Duration of Response (DOR) | 16.39 Months |
| Chemotherapy Category 1 | Duration of Response (DOR) | NA Months |
Secondary
Objective Response Rate (ORR)
Time frame: Two consecutive occurrences of complete or partial response >/=4 weeks apart (up to approximately 4 months)
Population: The ITT population included all Cat. 1 randomized participants, whether or not the assigned study treatment was received. Cat. 2 endpoints were exploratory and not analyzed.~NA: Participants had no lesions to report at baseline NE: Post-baseline assessments reported not evaluable for any reason or if SD assessment was within 6 weeks of baseline Missing: No post-baseline assessments available
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Molecularly-Guided Therapy (MGT) Category 1 | Objective Response Rate (ORR) | Complete response (CR) | 4.9 Percentage of participants |
| Molecularly-Guided Therapy (MGT) Category 1 | Objective Response Rate (ORR) | Partial response (PR) | 12.9 Percentage of participants |
| Molecularly-Guided Therapy (MGT) Category 1 | Objective Response Rate (ORR) | Stable disease (SD) | 44.5 Percentage of participants |
| Molecularly-Guided Therapy (MGT) Category 1 | Objective Response Rate (ORR) | Non-CR/Non-PD | 7.1 Percentage of participants |
| Molecularly-Guided Therapy (MGT) Category 1 | Objective Response Rate (ORR) | Not Applicable (NA) | 2.5 Percentage of participants |
| Molecularly-Guided Therapy (MGT) Category 1 | Objective Response Rate (ORR) | Progressive disease (PD) | 17.8 Percentage of participants |
| Molecularly-Guided Therapy (MGT) Category 1 | Objective Response Rate (ORR) | Not evaluable participants | 0.6 Percentage of participants |
| Molecularly-Guided Therapy (MGT) Category 1 | Objective Response Rate (ORR) | Missing participants | 9.8 Percentage of participants |
| Chemotherapy Category 1 | Objective Response Rate (ORR) | Missing participants | 11.8 Percentage of participants |
| Chemotherapy Category 1 | Objective Response Rate (ORR) | Complete response (CR) | 3.6 Percentage of participants |
| Chemotherapy Category 1 | Objective Response Rate (ORR) | Not Applicable (NA) | 2.7 Percentage of participants |
| Chemotherapy Category 1 | Objective Response Rate (ORR) | Partial response (PR) | 4.5 Percentage of participants |
| Chemotherapy Category 1 | Objective Response Rate (ORR) | Not evaluable participants | 0 Percentage of participants |
| Chemotherapy Category 1 | Objective Response Rate (ORR) | Stable disease (SD) | 49.1 Percentage of participants |
| Chemotherapy Category 1 | Objective Response Rate (ORR) | Progressive disease (PD) | 21.8 Percentage of participants |
| Chemotherapy Category 1 | Objective Response Rate (ORR) | Non-CR/Non-PD | 6.4 Percentage of participants |
Secondary
Overall Survival (OS)
Time frame: From randomization to death from any cause (approx. 4 years)
Population: The ITT population included all Category 1 randomized participants, whether or not the assigned study treatment was received. Endpoints for Category 2 were exploratory and were not included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Molecularly-Guided Therapy (MGT) Category 1 | Overall Survival (OS) | 15.18 Months |
| Chemotherapy Category 1 | Overall Survival (OS) | 12.78 Months |