Carboplatin, Paclitaxel, and Everolimus in Treating Patients With Previously Untreated Cancer of Unknown Primary

Study Overview
=================
Brief Summary
-----------------
RATIONALE: Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. PURPOSE: This phase II trial is studying how well carboplatin given together with paclitaxel and everolimus works in treating patients with previously untreated cancer of unknown primary.

Detailed Description
-----------------
OBJECTIVES: Primary Evaluate the response rate in patients with previously untreated cancer of unknown primary treated with the combination of carboplatin, paclitaxel, and everolimus. Secondary Assess time to progression, overall survival, duration of response, and time to treatment failure in patients treated with this regimen. Determine adverse events of this regimen in these patients. Perform descriptive correlative studies to determine response of specific tumor types, identified by the Origin-FFPE test, to this regimen. OUTLINE: This is a multicenter study. Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 1. Patients also receive oral everolimus once daily on days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients' tumor tissue samples from the most recent biopsy are analyzed for correlative studies, including gene expression profiling by Origin-FFPE test. After completion of study therapy, patients are followed up every 3 months until disease progression, and then every 6 months for up to 3 years.

Official Title
-----------------
A Phase II Study of Carboplatin (CBDCA), Paclitaxel (TAXOL), and Everolimus (RAD001) in Previously Untreated Patients With Measurable Disease With Cancer of Unknown Primary (CUP)

Conditions
-----------------
Carcinoma of Unknown Primary Origin

Intervention / Treatment
-----------------
* Drug: carboplatin
* Drug: everolimus
* Drug: paclitaxel


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Histological confirmation of metastatic adenocarcinoma, poorly differentiated non-small cell carcinoma, or poorly differentiated squamous carcinoma Adequate FFPE tissue or re-biopsy planned after registration but prior to treatment Measurable disease as defined; for patients having only lesions measuring at least 1 cm to =< 2 cm must use spiral computed tomography (CT) imaging for both pre- and post-treatment tumor assessments; disease that has received prior radiation (performed for palliative reasons) cannot be used for measurable disease Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Hemoglobin (Hgb) >= 9.0 g/dL Absolute neutrophil count (ANC) >= 1,500/uL Platelet count >= 100,000/uL Total bilirubin =< upper limits of normal (ULN); if liver metastases are present, total bilirubin =< 2 x ULN Aspartate aminotransferase (AST) =< 2.5 x ULN; if liver metastases are present, AST =< 5 x ULN Creatinine =< 1.25 x ULN; if > 1.25 x ULN calculated creatinine clearance must be >= 60 ml/min Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Provide informed written consent Willingness to return to NCCTG enrolling institution for follow-up Willingness to abstain from eating grapefruit or drinking grapefruit juice for the duration of the study Exclusion Criteria Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception; note: adequate contraception must be used throughout the trial and for 8 weeks after the last dose of RAD001, by both sexes Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens History of any of the following: Known to be human immunodeficiency virus (HIV) positive Known prior/current history of hepatitis related to hepatitis B or hepatitis C Uncontrolled intercurrent illness including, but not limited to the following: Ongoing or active infection (acute or chronic) Symptomatic congestive heart failure Unstable angina pectoris Cardiac arrhythmia Severely impaired lung function Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN (note: optimal glycemic control should be achieved before starting trial therapy) Liver disease such as cirrhosis or severe hepatic impairment Psychiatric illness/social situations that would limit compliance with study requirements Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm =< 4 weeks prior to registration Other active malignancy =< 5 years prior to registration; EXCEPTIONS: non-melanotic skin cancer or carcinoma-in-situ of the cervix; NOTE: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer Untreated brain metastases; NOTE: patients with treated, stable brain metastases for at least 12 weeks prior to study entry are eligible for enrollment Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection) Active, bleeding diathesis Receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed Currently on enzyme inducing anti-convulsants (EIACs) or other strong inducers or strong inhibitors of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) Current use of warfarin (Coumadin); EXCEPTION: current use of low-molecular weight heparin is allowed Known to be HIV positive Inoculated with live attenuated vaccines =< 2 weeks prior to registration; note: close contact with those who have received attenuated live vaccines should be avoided during treatment with everolimus; examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines =< 4 weeks from major surgery; note: for this study, diagnostic laparoscopy (without other intervention) and/or biopsies (needle aspirate, core biopsy, open biopsy, etc.) are not considered major surgery

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (carboplatin, paclitaxel, and everolimus)<br>Patients receive carboplatin IV over 30 minutes and paclitaxel IV over 3 hours on day 1. Patients also receive everolimus PO QD on days 1, 8, and 15. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: carboplatin<br>* Given IV<br>Drug: everolimus<br>* Given PO<br>Drug: paclitaxel<br>* Given IV<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Confirmed Tumor Responses | Confirmed tumor response was defined to be either a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 4 weeks apart. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; | First 6 Cycles of treatment (an average of 6 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Overall survival was defined as the time from study enrollment to the time of death from any cause or last follow-up. | Time from registration to death or last follow-up (up to 3 years) | 
| Progression-free Survival | The progression-free survival (PFS) was defined as the time from date of registration to the documentation of disease progression or death as a result of any cause, whichever comes first. | Time from registration to the disease progression or death (up to 3 years) | 
| Duration of Response | Duration of response was defined for all evaluable participants who have achieved an objective response as the date at which the participant's objective status is first noted to be either CR or PR to the date progression is documented. | Up to 3 years | 
| Time to Treatment Failure | Time to treatment failure was defined to be the time from the date of registration to the date at which the participant is removed from treatment due to progression, adverse events, or refusal. | Up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Newly Diagnosed Carcinoma of Unknown Primary Origin, Squamous Cell Carcinoma of Unknown Primary Origin, Undifferentiated Carcinoma of Unknown Primary, newly diagnosed carcinoma of unknown primary