Personalized Medicine Study (Survey and Analysis): Protocol

 

 

Protocol Contents

 

Protocol Title

Abstract

Background and Rationale

Study Aims

Experimental Design and Schema

Administrative Organization

Inclusionary Criteria

Exclusionary Criteria

Sample Size and Analysis

Study Endpoints

Study Procedures

Informed Consent

Recruitment

Screening

Risk Disclosure

Confidentiality

Study Intervention

Safety Monitoring Plan

Analysis Plan

Funding

Literature Cited

 

In this observational survey, patients’ tumor cells will be tested prospectively in vitro by the Principal Investigator for susceptibility to specific chemotherapy agents. Test results will be provided to attending physicians in advance of treatment selection by those physicians. Physicians will consider the full range of known clinical factors, in accordance with standard medical practice, and will select for each patient a treatment which is appropriate.  Treatment selection will be guided by each physician’s best clinical judgment.  Treatments will be administered as in the normal course of patient management.  In cases where treatment includes drugs to which patient tumor cell susceptibility had been evaluated prospectively by the Principal Investigator, clinical outcomes of patients will be reported to the Principal Investigator who will then attempt to correlate patient clinical outcomes with in vitro tumor cell susceptibility as observed individually for each patient. 

I. Background and Rational

Despite the introduction of several new anti-cancer drugs over the past two decades, including the so-called “targeted therapy” agents, overall rates of cure for many cancers have remained largely unchanged.  While improvements in response and survival have been achieved in some diseases and in some patient populations, these typically are modest and are confined to a handful of situations.  Traditional clinical trials of pharmaceuticals in which patients are randomized to receive treatment have failed, in most cases, to identify a single “best” drug regimen to administer to all patients sharing a specific cancer diagnosis.  This is particularly true in settings of metastatic and recurrent disease.  And yet individual patients representing all types and stages of cancer are shown occasionally to benefit substantially from both targeted agents and from more traditional drugs.  Among individual patients, long term remissions and even cures are reported.  This suggests that individualizing drug selection for each patient by incorporating into the selection process some number of patient-specific factors could be useful.  Indeed, the term “Personalized Medicine,” often through the study of molecular factors potentially predisposing susceptibility of a patient’s illness to treatment with specific drugs, has become a principal focus in oncology.  This approach ties into a broader challenge currently confronting patients, physicians, drug companies, insurance carriers, and the FDA.  Presented with an expanding array of expensive and potentially toxic treatments that provide benefit to some but not all patients, a better method must be devised to match patients with drugs which are most likely to help them.  This is especially true of the theoretically-promising but financially-costly targeted therapy drugs.

Speaking to this issue, an editorial in Journal of Clinical Oncology (Sledge, J Clin Oncol Sledge 23:1614, 2005) suggests that no therapy can be deemed truly “targeted” if the target cannot be “measured,” in the clinic or in the laboratory.  The editorial states that such measurement can be qualitative or quantitative but that there must always be something measureable, ostensibly allowing for reliable selection of patients who will benefit from the therapies.  The author suggests that, with no reliable means to identify probable responders to drugs, “...research into targeted therapies will grind to a halt.”  He cites the fact that “breast cancer clinical trials increasingly enroll larger populations of patients to find smaller differences in outcome,” and concludes, “An unselected approach has the real potential for throwing away valuable drugs.”

Concurrent with efforts aimed at improved patient selection, the drugs themselves are undergoing further scrutiny as physicians and investigators devise ways to increase drug effectiveness.  Numerous clinical trials are underway in which traditional cytotoxic drugs and targeted therapy drugs, such as kinase and angiogenesis inhibitors, are combined to enhance anti-tumor effect.

We have found that, when combined in vitro against specific populations of viable tumor cells, the complementary properties of these drugs occasionally produce marked synergistic effects in which modest single agent activity in vitro increases substantially with the addition of a second or third agent.  Particularly striking are anti-angiogenic effects produced by certain combinations of anti-kinase and anti-angiogenic drugs.  This is consistent with results of studies in which Folkman et al showed how combining two anti-angiogenic agents, endostatin and angiostatin, greatly increased anti-angiogenic activity relative to that achieved by each drug alone.

However, efforts to individualized drug selection as well as research studies of angiogenesis and other targeted single agent and combination therapies have been hindered by limitations in the clinical relevance of laboratory model systems.  We have developed new methods for assessing the cytotoxic activity of anti-kinase agents and also for measuring dead microvascular cells in clinical tissue, fluid, and blood specimens.  We applied this system to make several potentially novel observations relating to cancer pharmacology and biology.  Among other things, we documented crossover activity in which drugs, ostensibly in different classes, exert both anti-tumor and anti-angiogenic effects.  We have also shown that these effects can be enhanced in some cases by combining certain of the drugs and that the extent of mitigation of drug effect can be measured in our assay system.  Importantly, we have also observed that anti-tumor and anti-angiogenic effects are patient-specific as well as disease-specific, thereby accurately reflecting the reported clinical experience.

Once again, the goal of individualizing treatment is broadly shared throughout the medical community.  Therefore, much interest (and funding) recently has been directed  toward development of gene and protein-based tests.  Gene and protein testing are indirect approaches to chemotherapy selection which examine a single process within the cell or a relatively small number of processes.  Their aim is to determine only if there is evidence of a theoretical predisposition to drug susceptibility.  In this regard, gene and protein testing are “static profiling” approaches.

We favor a “functional profiling” approach involving real-time assessment of living cancer and endothelial cell behaviors in the presence or absence of anti-cancer or anti-angiogenic drugs.  This method accounts not for only for the existence of genes and proteins but also for their functionality and for their interaction with other genes, other proteins, and other processes occurring within the cell.

Gene and protein testing involve the use of non-viable, formalin-fixed cells that are never exposed to chemotherapy drugs.  Gene and protein tests cannot, therefore, elucidate issues relating to drug uptake or show if the drug will be excluded from the cell before it can act or what changes will take place within the cell if the drug successfully gains entry.  Neither can gene or protein tests discriminate among the activities of different drugs within the same class.  Instead gene and protein tests assume that all drugs within a certain class will produce essentially the same effect in the presence of a specific molecular expression even though clinical experience suggests that this is not the case.  Nor can gene or protein tests detect drug synergy in combination.

In contrast, functional tumor cell profiling assesses the net result of all cellular processes occurring in real time when viable cancer cells actually are exposed to specific anti-cancer drugs.  Functional profiling therefore can discriminate differing anti-tumor and anti-angiogenic effects produced by  different drugs nominally within the same class.  Functional profiling, as we propose to use it in this trial, can also identify synergies in drug combinations.

We therefore propose to use these functional tumor and endothelial cell profiling systems to identify potentially clinically-active treatments on a patient by patient basis, to observe rates of response, progression-free survival, and overall survival observed among patients receiving assay-directed treatments, and to compare these with rates of survival as reported by the National Cancer Institute Surveillance Epidemiology and End Results (SEER) program for patients with similar diagnoses and other closely-matched clinical characteristics.  

II. Study Aims

• This study will seek to determine if clinical outcomes, as defined by objective response to treatment and by progression-free and overall patient survival can be correlated with patterns of endothelial cell and tumor cell susceptibility, observed prospectively, in vitro, to specific single agent and combination chemotherapy drugs.   

III.  Experimental Design and Schema.

• This is an observational, single-arm, non-randomized, non-blinded study.

• Patients accrue to the study by means of physician referral.

• Patients are screened for eligibility.

• Specimens of viable tumor cells are collected from qualifying patients at facilities approved by Larry Weisenthal, study Principal Investigator (PI).

• Specimens are shipped while fresh and viable to Weisenthal Cancer Group.

• Specimens are accessioned to the study and are prepared for in vitro MVV (endothelial cell)  and also (secondarily) for functional tumor cell profiling in order to discriminate anti-vascular drug effect from anti-tumor drug effect. 

• A panel of candidate chemotherapy drugs is selected for each patient.

• Tumor cells are exposed to candidate drugs. 

• Drug effects are assessed by the P.I..

• In vitro MVV endothelial and functional tumor cell profiling results are reported prospectively to the referring physician, considers the full range of clinical factors, applies his or her best clinical judgment, and designs and administers therapy in accordance with normal medical practice.

• Routine clinical assessment and ongoing surveillance occur at intervals and by methods customarily applied in the context of each patient’s clinical situation.

• Results of these assessments are reported to the PI for interpretation, statistical analysis, peer-review, and reporting.

• Study patients are free at any time to leave the study entirely and/or to receive  any form of treatment, whether or not such treatment has been assessed prospectively by functional whole cell profiling assay. 

IV. Administrative Organization

• Principal Investigator:  Larry Weisenthal, M.D., Ph. D.

• Study Coordinator:  Constance Rueff Weisenthal, M.T., Laboratory Manager, Weisenthal Cancer Group

• Central Laboratory: Weisenthal Cancer Group, 16521 Burke Lane, Huntington Beach, CA.

V. Study population

             Inclusionary criteria include:

• Diagnosis of cancer

• Patient has viable tumor cells that are accessible by biopsy

• Patient is ECOG performance status 0 or 1 and has no contraindications for receiving traditional, cytotoxic chemotherapy, chemotherapy with anti-kinase “targeted” agents, or antiangiogenic agents.

• Patient’s physician is qualified and willing to select and administer chemotherapy  and, if treatment selection by the treating physician includes drugs prospectively evaluated by the P.I., to report patient clinical progress reports to the P.I..

• Patient consents to providing follow-up data concerning treatments and treatment results, whether on study or off study, for online posting, until death, with best effort privacy protection (see section V, below).

B.      Exclusionary criteria include:

• No biopsiable tumor cells

• Physical condition excludes the possibility of receiving chemotherapy

• Treatment selected by patient’s physician does not include drugs evaluated prospectively by the P.I..

• Patient or patient's physician is not willing or not able to provide follow up data for online posting (see a. vii, above)

VI. Sample Size Determination and Power Analysis

• Target accrual is 50 patients.

VII. Study Endpoints

• Response (As determined by physical exam, palliation of symptoms, biomarkers of disease, radiology, blood counts, and other qualitative and quantitative measures which are widely-accepted within a specific cancer diagnosis).

• Progression-free survival (Same as above)

• Overall survival

VIII. Study Procedures

• Patient selection procedures

                  - All cancer diagnoses will be considered.

                  - Inclusionary and exclusionary criteria are as outlined above.

• Recruitment procedures

                 - Recruitment will occur though physician referral.

C.  Informed Consent

• Each patient will be required to provide Weisenthal Cancer Group with an executed permission and consent form for that patient.

• Weisenthal Cancer Group will maintain copies of executed permission and consent forms as part of each patient’s laboratory record.

• Executed permission and consent form copies will be provided to each patient’s physician by Weisenthal Cancer Group.

• Permission and Informed consent will be obtained by each patient’s physician, by the survey research team, or by a member of the physician’s staff.

      Please click here to review a copy of the Patient Information and Consent Form.

 D.  Advertising Plan

• The clinical trial will be advertised on the Weisenthal Cancer Group commercial website: www.weisenthalcancer.com as well as on Dr. Larry Weisenthal’s cancer blog: www.weisenthal.org

• An information sheet will be distributed to participating investigators in order to facilitate communication with patients whom the investigators deem to be qualified as potential study participants.

E.  Screening procedures

• Study candidates will be screened principally by referring physicians, who will confirm diagnosis, accessibility of viable cancer cells, and fitness to receive chemotherapy.

• Baseline assessment of the patient’s physical condition will be performed, to include stage of disease, tumor burden measurements, symptoms present, previous treatments received, and overall physical condition.  This information will be provided to Weisenthal Cancer Group, which will maintain it as part of the patient’s laboratory record.

• Further screening will occur by telephone, either directly with the patient or with the patient’s physician, by Dr. Weisenthal, Principal Investigator and/or by Constance Rueff Weisenthal, Weisenthal Cancer Group Laboratory Manager and Study Coordinator.  The purpose of this screening will be to verify information submitted by the physician and to confirm that the patient satisfies medical inclusionary criteria and is competent to give consent to participate in the study.

F.  Risk Disclosure

• Patients will be apprised in writing of all potential risks and hazards, including physical and financial risks, prior to entry onto the study.

   

G. Confidentiality     

• Information pertaining to specific patients obtained through screening and throughout the study will be maintained as part of the patient’s laboratory record to be included within the patient’s official laboratory chart and stored in filing cabinets located in a secure, locked area within Weisenthal Cancer Group to which only participating investigators, the study coordinator, and other essential members of the research team have access.

• Information pertaining to prospective patients who fail to meet inclusionary criteria but who ultimately receive functional tumor cell profiling analysis on a non-investigational basis will be held in confidence and stored as described above

• Information pertaining to prospective participants who fail to meet inclusionary criteria and who do not receive functional tumor cell profiling analysis will be held in confidence and stored as described above

H.  Study Intervention.

• Any patient may, at any time, remove him or herself from the study without cause.  Such patients will still be allowed full access to results of functional tumor cell profiling analyses which were performed for them and to any drugs and/or regimens suggested by those analyses which are available to them through their own physicians and resources.  Patients will be asked, however, to continue to provide follow-up information for posting on the above website.

I.  Safety Monitoring Plan 

• Adverse events are defined as side-effects relating to individualized chemotherapy drug treatments received by the patient within the context of the study when such complications exceed those which normally are associated with treatment the various drugs and/or which are deemed acceptable by both the physician and patient. 

• Patients’ physicians will identify, document, and report adverse events immediately to the Principal Investigator at Weisenthal Cancer Group.

• In addition, participating investigators will be asked to report all drug-related side effects along with any other adverse medical outcomes observed in the course of routine patient follow-up.  This information will be reported to both the study monitor and to the Principal Investigator who will review it in context with the patient’s clinical situation and in comparison with complications reported for other patients in the study.  Additionally, we will maintain a separate section on the study website reporting adverse effects.

• Patterns of suspected drug-related toxicity or of any other medical complication observed among study patients will be reported immediately to all participating physicians and will be appended to all subsequent patient and physician risk disclosures, as well as  being posted to the website.

J.  Analysis Plan

In addition to reporting all study results, real time, on the web site, the investigators will extract data for analysis and publication.

K.  Funding

• No funding will be accepted by the study investigators from any outside source, to include drug companies and academic institutions to ensure that drug selections and treatment recommendations provided individually for each patient are free from internal bias or outside influence. 

• Patients will be billed for testing and treatment costs in the normal manner, in which patients are billed for medical services separately by each healthcare entity which provides services.

• No extra tests, treatments, or other medical services will be required beyond those which otherwise are routinely applied and are appropriate to each patient's clinical situation.

• It is expected that Medicare and some private insurance carriers will reimburse patients for some portions of some drugs and/or laboratory and medical services received by patients within the context of the study.  However, patients should expect that many if not most of the costs for these drugs and services will not be reimbursed by third party payors and will therefore accrue to the patient in the normal manner.  

• Administrative costs of the study to include study monitoring, data collection, analysis, and management, patient and physician communications, and other study costs not directly related to the patient’s clinical care are not borne by the patient.  These costs will be paid by Weisenthal Cancer Group.