Advocacy or Vaccines > Concerns About Randomized Vaccine Trials 

Last update: 05/02/2013

Participant-Centered Perspective | NCI/Genitope Protocol Summary | References
 
Also see: Comparing Vaccines

"Because it would be morally indefensible for researchers to give study participants an intervention known to be substandard, genuine uncertainty must exist about which of the potential treatments is better to justify a clinical trial. But clinical equipoise relies on clinicians and scientists to decide when there is enough uncertainty to warrant a clinical trial. Due in part to HIV/AIDS activists efforts, support is growing for adopting community equipoise as the relevant standard. According to this standard, a trial should be conducted only if affected people agree with medical experts that there is genuine uncertainty about which intervention is better. Thus, for a trial to be justified, people facing the actual consequences of illness must be uncertain about the preferred approach and want to know which is better. The concept also supports community participation in determining when there is enough uncertainty about the risks and possible benefits of an active agent to justify assigning some participants to the placebo group." 

p49 “When Science offers Salvation” - Rebecca Dresser 

Participant-Centered Perspective

The urgent need for new treatments cannot be overstated for patients with indolent lymphomas as standard chemotherapy treatments have had no significant impact on survival [4]. We also know from experience that the design of clinical trials dramatically affects enrollment, and could impact on the survival chances of the participants. For patients and caregivers, this is not an academic discussion. Therefore, I hope that you will read th list of concerns within very carefully, and give consideration to the proposals and questions this paper contains.

About the Idiotype Vaccine

Briefly, an Idiotype vaccine is created by isolating a unique protein (Idiotype) thats expressed on each lymphoma cell (clonally expressed). A biopsy is required to create a custom tumor vaccine in order to isolate and expand this protein. The idiotype (Id) protein is then fused with another protein (such as KLH) with the purpose of making it "visible" or "recognizable" by the immune system. After the vaccine is created and administered, an immune stimulant, typically GM-CSF, is also given to the patient to boost immune function and increase the chances of recognition of the target proteins. So far, investigators have chosen chemotherapy as the pretreatment of choice in the vast majority of Id vaccine trials, as its generally considered important to reduce tumor burden prior to the vaccine. For this reason, a rest period is required before the patient can receive the vaccine. 

Patient Interest in Idiotype Vaccines is High, But A Good Number of Eligible Patients Are Not
Participating in Current Vaccine Randomized Vaccine Trials

Patients are excited about the Idiotype technology, which is impressive. For example, a clinical phase II study to test a version of the Id vaccine at Stanford filled in one weeks time. But that study did not require pretreatment with chemotherapy, and it was not randomized. It demonstrates, importantly, that the level of interest in a study is determined by the design of the study, and on the patients assessment (often influenced by consultation with their treating physician) that the treatment can help them without compromising future treatment options, or by exposing themselves unnecessarily to treatment toxicity and risks.

Considering the promising results to date, you might expect patients with an incurable disease to be excited about the initiation of large phase III studies to test two promising versions of the Idiotype vaccine.  But, apparently each study is  enrolling patients slowly, and we think that the consequences of the delays are tragic. And so it's imperative to carefully identify the obstacles to enrollment in these studies and find a remedy. 

About the Design of Vaccine Trials:  An Important Paper Lacks the Patients Perspective

It was with great interest that I read Clinical Trial Design for the Early Clinical Development of Therapeutic Cancer Vaccines [3]. The paper focused, understandably, on important design consideration that are unique to vaccines: a) their relative safety; b) the ideal participants; c) establishing end pointstumor shrinkage, delayed time to progression, immunologic end points, and molecular markers; d) efficient screening of vaccine regimens; e) the difficulties with historical comparisons; f) the need for randomized studies; g) and factorial designs.

However, the authors did not address the patients perspective in the paper despite the following: 1) Patient participation is required to get meaningful answers to scientific questions. 2) We know that under the best of circumstances it is not easy to enroll patients in trials, and that about two percent of cancer patients participate. 3) The primary motivation of patients considering a trial is to treat their disease, not to answer scientific questions. 4) Patients have one life to experiment with, so they will avoid studies that unnecessarily preclude future treatment options or that are not perceived to be in their best interest. We assert that failing to address these factors when designing studies will hinder the science as certainly as any  consideration described in this paper.

Patient Concerns About Current Randomized Vaccine Studies

1. In each randomized study for patients in the control group the biopsy has no therapeutic purpose: Each trial requires a biopsy to obtain fresh tumor sample. This procedure carries some risk, such as infection or permanent Lymphedema.
    
2. For the control group, pre-treatment with chemotherapy could compromise future treatment options: The chemotherapy agents required by these protocols have known side effects, some of which are serious and potentially irreversible. Myelosuppression is among the side effects that can compromise or limit the patients ability to benefit optimally from future immunotherapies. This is an important consideration, as all patients in the study will receive chemotherapy, but not everyone will receive the vaccine. We know that the designers of vaccine trials are aware of the potential negative impact of standard treatments: "End-stage patients without intact immune systems may have very little likelihood of benefit or toxicity from a tumor vaccine.[3]"
    
3. For the control group, the chosen pre-treatment protocols (CVP / PACE respectively) do not seem ideal in many circumstances as a frontline treatment. Single agent chlorambucil is often indicated at low doses for frontline treatment, and often achieves good results with minimal toxicity.  And Rituxan as front-line treatment can also be effective without compromising immune function as comprehensively as combination chemotherapy. When strong measures are indicated because of high tumor burden or when the patient has clinically aggressive follicular NHL, the patient and their physicians will often consider CHOP + Rituxan  or FND-R over CVP or PACE.  
    
4. We don't believe that collective and theoretical equipoise exist for the compared protocols. "Ethical justification for starting a clinical trial requires at the outset an accurate statement of "no difference" regarding the two or more agents to be compared." [7] It is a well known that physicians are relied upon to guide most patients into trials. The fact of slow accrual in these randomized studies may demonstrate that collective equipoise does not exist among treating physicians, else the studies would be better populated. Theoretical equipoise cannot be established either, as we have good data showing efficacy of the vaccine in published studies and observed immune responses in earlier studies.
    
5. Future treatment decisions of many of the participants may become problematic: Because each study is blinded, the participants and their doctors will never be told if they received the Id vaccine or the control (KLH). Patients are concerned about how this will affect their ability to make informed treatment decisions when their disease recurs or progresses and they go off the study, and consider other studies.
    
6. It appears that the rationale for blinded studies is to discover if there is a survival benefit to the group receiving the vaccine. This was the reason given for not providing a crossover provision in the NCI/Genitope study. However, patients who relapse or progress after receiving the vaccine or the control will have opportunity to try multiple standard or investigational treatments as needed, including the same vaccine should it win approval, thus confounding assessment of survival. 
    
7. The study protocol unnecessarily limits the possible optimal use of the vaccine. It's plausible that revaccination at a later time can benefit patients who have had the vaccine. Neither protocol makes any stated provision to make and store extra vaccine. The hope that such a backup plan could be available in such an event is one of the attractive things about vaccine therapy, particularly because credible anecdotes indicate that booster vaccines have had apparent success in some cases.
    
8. In the NCI study, the requirement to get a complete response (CR) is a concern because there is data [5] showing that some patients may benefit from the vaccine even if they have measurable tumor burden. We submit that these patients should have the option to use the vaccine anyway and be followed in a separate study. By designing the study in this way, more patients have a chance to benefit from the vaccine, the investigators learn more, and the study will probably enroll patients more quickly. We cannot overlook that the vaccine treatment, unlike most cancer therapies, is considered safe based on ten+ years of use.
    
9. Undesirable study protocols delay patient accrual. Delays have serious consequences: The undesirable aspects of both trials, well known to patients in the online community, may profoundly slow accrual. Without patient participation we cannot answer important scientific questions, and we have no hope of assessing a promising treatmentperhaps the only treatment so far that has the potential to improve survival. [1, 2] Therefore, delays caused by trial design could well impact the survival of thousands of people. We should also emphasize the considerable financial costs that result from delays to the sponsors. Will this negatively impact the resolve of other pharmaceutical companies? Will they conclude from this example that its too difficult and too costly to develop other promising cancer therapies?
    
10. The NCI 00-C-0050 protocol descriptions may be misrepresenting the chance of getting the Id vaccine as 2 out of 3 patients. The study is recruiting approximately 563 patients. Its expected that about 375 will achieve a CR required to be eligible to receive the vaccine after chemotherapy. Of these patients, 2/3 will receive the Idiotype vaccine. Thus, approximately 44%, or about 250 patients will receive vaccine; 313 patients will not.
     
11. At least one promotion of the NCI 00-C-0050 study describes it as a comparison of two vaccines. We know that KLH (the adjuvant) alone has no chance to "educate" the immune system about the patient's unique tumor antigen. Currently, no investigators are treating (or investigating treating) patients with KLH or GM-CSF. The use of adjuvants and immune stimulants alone makes sense only when combined with the Id vaccine, and investigators have no expectation that the control "vaccine/placebo" will benefit the patients, else each arm of the study would have had an equal number of patients.
     

12. Finally, if the vaccines win FDA approval based on time to progression data in the next few years, participants who progress or relapse will want to know (and deserve to know) if they have received the vaccine or the placebo vaccine.  The drug sponsors and the FDA will then be faced with having to deny requests for this information in order to continue to collect data on long term survival.  Importantly, the Genitope study produces Idiotype vaccines for both arms of the study, so patients who relapse would be able to request compassionate use of the vaccine as well if it should win approval.  
    

Summary of concerns from a patient's perspective:

If I end up in the control group all of the following occurs: 

1. I've had surgery for no benefit, except to blind the study; 

2. I may have had less than optimal chemotherapy as front-line treatment - too much or too little; 

3. I may compromise my ability to benefit from future immunotherapies, including the vaccine should it win approval; 

4. I'm uncertain about my treatment history, which could affect my ability to enter other clinical trials.

NOTE:  We wish to underscore that the Genitope and NCI randomized vaccine studies may well be appropriate, if you (in partnership with your treating physician) determine that CVP or PACE is an appropriate frontline treatment in your current circumstance.  In other words, each of these studies may still be reasonable treatment decisions despite the many concerns we have about the design of these randomized studies.

We look forward to your about this important matter. 

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PROTOCOL SUMMARY
 
GENITOPE G2000-03 Protocol Details | NCI 00-C-0050 NCI (Kwak) Details

NOTE: The Genitope Study has completed enrollment as of April 200.4

This summary combines the NCI and Genitope Protocols and describes known differences.
 

• All patients have resection (surgery) of peripheral lymph node.
   

• All patients pretreated with chemotherapy (CVP for Genitope, PACE for NCI study)
   

• Only patients who receive a CR or a PR in Genitope study continue
   

• Only patients who receive a CR in NCI study continue
   

• Each study divides responders to pretreatment into one of two groups (arms)
   

• Arm I (1/3 of responders to pretreatment) receive the KLH and GM-CSF
   

• Arm II (2/3 of responders to pretreatment) receive Idiotype vaccine bound to KLH and GM-CSF

NOTE:  The KLH is bound to the Idiotype protein to make it more immunogenic. The GM-CSF is injected later to stimulate APC cells to improve chances of developing an immune response against the tumor antigen (the Idiotype protein thats unique to patients tumor).

• NCI OUTLINE:
  Arm I (Control): Patients receive autologous lymphoma idiotype vaccine and keyhole limpet hemocyanin (KLH) subcutaneously (SC) on day 1 and sargramostim (GM-CSF) SC on days 1-4.
   
  Arm II: Patients receive KLH and GM-CSF as in arm I. Vaccination repeats at 1, 2, 3, 4, and 6 months. Patients are followed every 3 months for 1 year and then every 6 months thereafter.
   

• GENITOPE OUTLINE:
  Arm I (Control): Patients receive autologous tumor-derived immunoglobulin idiotype conjugated to keyhole limpet hemocyanin (KLH) subcutaneously (SC) on day 1 and adjuvant sargramostim (GM-CSF) SC on days 1-4 of weeks 0, 4, 8, 12, and 24.
   
  Arm II: Patients receive KLH alone SC on day 1 and GM-CSF SC on days 1-4 of weeks 0, 4, 8, 12, and 24. Quality of life is assessed prior to first immunization, at 2-8 weeks after completion of immunizations, and then every 6 months for 3 years. Patients are followed every 3 months for 1 year and then every 6 months thereafter. Patients also enroll in a long-term follow-up study for an additional 5 years.

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References

1. Tumor-specific idiotype vaccines in the treatment of patients with B-cell lymphoma-long-term results of a clinical trial. Hsu FJ, Caspar CB, Czerwinski D, Kwak LW, Liles TM, Syrengelas A, Taidi-Laskowski B, Levy R.

2. Complete molecular remissions induced by patient-specific vaccination plus granulocyte-monocyte colony-stimulating factor against lymphoma.
Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA, Pennington R, Watson TM, Reynolds CW, Gause BL, Duffey PL, Jaffe ES, Creekmore SP, Longo DL, Kwak LW.

3. Clinical Trial Designs for the Early Clinical Development of Therapeutic Cancer Vaccines,
Clin Oncol 19:1848-1854,Richard M. Simon, Seth M. Steinberg, Michael Hamilton, Alland Hildesheim, Samir Khleif, Larry Wl Kwak, Crystal L. Mackall, Jeffrey Scholom, Suzanee L. Topalian, and Jay A. Berzofsky, J

4. A systematic overview of chemotherapy effects in indolent non-Hodgkin's lymphoma.
Brandt L, Kimby E, Nygren P, Glimelius B; SBU-group. Swedish Council of Technology Assessment in Health Care.

5. Induction of immune responses in patients with B-cell lymphoma against the surface-immunoglobulin
idiotype expressed by their tumors.
Kwak LW, Campbell MJ, Czerwinski DK, Hart S, Miller RA, Levy R.

6. Cancer therapy and the randomized clinical trial: good medicine? - Kaufman D.

7. Randomized clinical trials in periodontology: ethical considerations. - Levine RJ, Dennison DK.
 

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