Carcinoma
Conditions
Keywords
Carcinoma of Unknown Primary Site, Molecular profiling assay, Bevacizumab, Erlotinib, Paclitaxel, Carboplatin
Brief summary
This is a non-randomized Phase II study. Patients determined at initial diagnosis to have a carcinoma of unknown primary site (CUP) will have their treatment selected with the use of a molecular profiling assay. The assay will be performed on paraffin-embedded tumor tissue from a biopsy specimen. Patients given specific diagnoses (e.g., lung, pancreas, colon, breast, renal cell, prostate and ovarian cancer) will receive treatment regimens of proven activity. If no specific diagnosis is made with the molecular profiling assay, empiric chemotherapy with paclitaxel, carboplatin, bevacizumab and erlotinib will be administered.
Detailed description
The primary objective of the study is evaluate the impact of the molecular assay prediction on the efficacy of therapy for patients with carcinoma of unknown primary site (CUP). Investigators will use tumor profiling results to direct standard, site-specific first-line therapy for patients with CUP.
Interventions
DRUGPaclitaxel
175 mg/m2, 1-3 hour IV infusion Day 1
DRUGCarboplatin
AUC 6.0 IV Day 1
DRUGBevacizumab
15 mg/kg IV infusion Day 1
DRUGErlotinib
150 mg PO
OTHERTreatment determined by physician
Patients Assigned a Specific Diagnosis by the Molecular profiling Assay will have physician's choice therapy
Sponsors
Genentech, Inc.
SCRI Development Innovations, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have carcinoma of unknown primary site after the following diagnostic procedures have been performed and are unrevealing of a primary site: * Complete medical history and physical examination, * Complete blood counts, chemistry profile, * CT scans of the chest and abdomen, * Directed evaluation of any symptomatic areas, * PET scan (recommended). 2. Patients must have biopsy-proven metastatic carcinoma, with any of the following light microscopic histologies: * Adenocarcinoma, * Poorly differentiated adenocarcinoma, * Poorly differentiated carcinoma (all patients with poorly differentiated carcinoma must have immunoperoxidase stains to rule out other treatable malignancies \[e.g., lymphoma, neuroendocrine carcinoma\]), * Poorly differentiated squamous carcinoma. 3. Patients must have biopsy material available from a surgical biopsy, a core needle biopsy, or a fine needle aspiration biopsy to provide an adequate specimen (must be 40% tumor) for the molecular profiling assay. 4. An ECOG performance status 0, 1, or 2. 5. No previous treatment with any systemic therapy. 6. Measurable or evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST). 7. Laboratory values as follows: * WBC 4000/micro L, * Platelets 100,000/micro L, * Serum bilirubin \<1.5 times the institutional upper limits of normal (ULN), * Serum creatinine \< 2.0 mg/dL. 8. Patients with brain metastases are eligible only if all lesions have been controlled by surgical resection or radiation therapy, the patient is not steroid-dependent, and the patient meets all other eligibility criteria. 9. Patients must be \> 4 weeks from any major operative procedure. 10. To be eligible for the TREATMENT portion of the study, patients must have one of the five following diagnoses: colorectal, pancreas, NSCLC, ovary, renal cancer. 11. Patients must be able to understand the nature of this study and give written informed consent.
Exclusion criteria
1. Patients with the following specific syndromes are not eligible: * Patients with neuroendocrine carcinoma, * Women with adenocarcinoma isolated to axillary lymph nodes, * Women with adenocarcinoma isolated to peritoneal involvement, * Patients with carcinoma involving only 1 site, with resectable tumor at that site, or * Patients with squamous carcinoma limited to cervical, supraclavicular, or inguinal lymph nodes. 2. Patients with uncontrolled brain metastases and all patients with meningeal metastases. 3. Patients with insufficient biopsy material available for molecular profiling assay. 4. Women who are pregnant or lactating. All females of child-bearing potential must have a negative serum or urine pregnancy tests within 7 days prior to study treatment. 5. Men and women of childbearing potential are required to use effective methods of contraception during this study and for 6 months after ending therapy. 6. Patients who have received any other experimental drug within 28 days of starting treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | every 6-8 weeks (2 cycles) until death from any cause or lost to follow up, projected 18 months | Defined as the elapsed time from the start of treatment to the date of death from any cause or lost to follow-up. Participants lost to follow up were censored as of the last date known to be alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | at baseline | To evaluate the utility of the assay in identifying the tissue of origin in patients with carcinoma of unknown primary site (CUP), an archived tumor specimen was assayed upon study entry. If a tissue of origin was predicted by the assay, participants received standard site-specific therapy for that tumor type. When tissue of origin was not predicted by the assay, patients received standard empiric chemotherapy for CUP and were not followed further. If the assay was not completed due to inadequate amount of tumor in the biopsy specimen, patients were not treated on the study. |
Countries
United States
Participant flow
Recruitment details
Between October 2008 and December 2011, 289 subjects in the United States with CUP were enrolled and had a molecular assay of biopsy tissue. 252 (87%) subjects had a successful assay performed; 223 subjects were treated and 29 were withdrawn (16 no longer met eligibility criteria and 13 were removed because of patient decision).
Pre-assignment details
252 subjects had successful assays. 223 subjects were treated and 29 were withdrawn prior to treatment. 194 received assay-directed therapy; 29 received empiric CUP therapy. Patients receiving assay-directed therapy were divided into 2 groups: 1) more responsive tumour type; and 2) less responsive tumour type.
Participants by arm
| Arm | Count |
|---|---|
| Patients With Tumor Assays Performed Of 289 patients initially enrolled, 252 had successful assays performed. 37 patients had insufficient tissue for assay and came off study. | 252 |
| Total | 252 |
Baseline characteristics
| Characteristic | Patients With Tumor Assays Performed |
|---|---|
| Age, Continuous | 64 years |
| Region of Enrollment United States | 252 participants |
| Sex: Female, Male Female | 136 Participants |
| Sex: Female, Male Male | 116 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 74 / 223 |
| serious Total, serious adverse events | 30 / 223 |
Outcome results
Primary
Overall Survival
Defined as the elapsed time from the start of treatment to the date of death from any cause or lost to follow-up. Participants lost to follow up were censored as of the last date known to be alive.
Time frame: every 6-8 weeks (2 cycles) until death from any cause or lost to follow up, projected 18 months
Population: Of 223 treated patients: 194 received assay-directed therapy; 29 received empiric CUP therapy. The 194 patients who received assay-directed therapy were separated into groups based on predicted responsiveness of the tumor type for further analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| More Treatment Responsive | Overall Survival | 13.43 months |
| Less Treatment Responsive | Overall Survival | 7.62 months |
Secondary
Number of Participants With a Tissue of Origin Successfully Predicted by the Assay
To evaluate the utility of the assay in identifying the tissue of origin in patients with carcinoma of unknown primary site (CUP), an archived tumor specimen was assayed upon study entry. If a tissue of origin was predicted by the assay, participants received standard site-specific therapy for that tumor type. When tissue of origin was not predicted by the assay, patients received standard empiric chemotherapy for CUP and were not followed further. If the assay was not completed due to inadequate amount of tumor in the biopsy specimen, patients were not treated on the study.
Time frame: at baseline
Population: Of 252 participants analyzed, the assay correctly predicted the tissue of origin in 247 patients (98%). The predicted tissue of origin could not be determined in 5 participants (2%).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Gastroesophageal | 10 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Kidney | 9 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Liver | 8 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Sarcoma | 6 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Cervix | 6 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Biliary tract (gallbladder, bile duct) | 52 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Urothelium | 31 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Colorectum | 28 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Non-small cell lung | 27 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Pancreas | 12 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Breast | 12 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Ovary | 11 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Neuroendocrine | 5 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Prostate | 4 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Germ cell | 4 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Skin, squamous | 4 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Carcinoid, intestine | 3 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Mesothelioma | 3 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Thyroid | 2 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Endometrium | 2 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Melanoma | 2 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Skin, basal-cell | 2 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Lung, small-cell | 1 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Lymphoma | 1 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Head and Neck | 1 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | Adrenal | 1 participants |
| More Treatment Responsive | Number of Participants With a Tissue of Origin Successfully Predicted by the Assay | unclassifiable | 5 participants |