Speakers described the process by which protocols were developed and funded for the study of a specific therapeutic agent (shark cartilage) and a comprehensive and integrative intervention (Dr. Nicholas Gonzalez’s dietary and enzymatic treatment of pancreatic cancer). During this session, specific mechanisms of funding (e.g. through supplements to Center grants), as well as the step-by-step development of protocols, were outlined.

Dr. Greenblatt’s presentation centered on the use of shark cartilage for cancer treatment and the process by which a given manufacturer was selected to supply product for further clinical trials.

This project is primarily funded by the NCI, in collaboration with various other organizations and cancer treatment centers.

By April 1998, it was recognized that there was a large number of cancer patients who were using shark cartilage for cancer treatment. Therefore, NCI began the process of obtaining shark cartilage from companies and designing clinical trials. The NCI assessed a number of shark cartilage manufacturers and their products in order to identify potential sources for large scale production and use in clinical trials.

This evaluation process examined a wide variety of aspects of the shark cartilage product, including:

• species of shark from which cartilage was derived
• how product was standardized from lot to lot
• freedom from hazardous chemicals
• ability to provide enough product
• information on possible placebo
• manufacturing process
• certificate of analysis
• recommended dose
• product purity
• stability
• potency

Four manufacturers responded and their applications were reviewed by a committee of many different experts. One manufacturer was eventually selected: AEterna Laboratories.

Recently promoted to Medical Director of AEterna Laboratories, based in Quebec city,

Dr. Champagne presented issues regarding formulation, preclinical data and clinical research aspects of shark cartilage.

Raw material supply: small, deep sea sharks normally used for human consumption that are caught by fishermen who remove the meat for human consumption, then discard the cartilage.

The product name is AE941. It is a standardized aqueous extract of shark cartilage and it is widely believed to be a source of anti-angiogenic agent. AEterna laboratories has carried out extensive pre-clinical in vivo and in vitro tests. They have revealed that AE941 has potent anti MMPs activity, antitumor and antiangiogenic activity, as determined in the DH3 model of advanced breast carcinoma, Lewis lung carcinoma and other models.

AE941 has been tested in three therapeutic areas:

Oncology, on solid tumors (470 patients)

Dermatology, for treatment of psoriasis (49 patients)

Ophthalmology, for management of macular degeneration (10 patients)

Trials using shark cartilage alone have been carried out on patients with lung, breast or prostate cancer, in phase I or II trials. From phase I, the dose of 240 cc per day was selected. Phase II was then conducted using 240 cc per day. The majority of patients had non-small cell lung cancer (NSCLC), stages I through IV. All had previously received chemotherapy or radiotherapy and had exhibited cancer progression when they entered the trial. Even though the objective of the study was not to assess efficacy, Dr. Champagne observed substantial improvement of various parameters tested, such as disease progression, weight loss, etc. Extended treatment periods were pursued by many patients. Although this part of the study lacked statistical relevance due to the reduced number of patients, a number of interesting anecdotal cases were reported.

Another trial was conducted on other types of cancer, most commonly lung, breast, kidney, colon, ovarian and pancreas, either alone or in combination with chemotherapy. Presented in more detail was a series of renal carcinoma cases treated with kidney cancer, in some instances metastatic. Treatment in each case had been carried out for many months. Dr. Champagne reported considerable progress in each case.

Phase III of NSCLC is underway, as well as phase II of other cancers, such as melanoma.

Dr. Winn described the outline of a clinical trial. Phase I is aimed at determining the safety of the treatment. Phase II is aimed at determining if the product has biological activity. If it does, then the trial moves on to phase III, where issues such as efficacy are assessed.

The trial described by Dr. Winn was double-blind, and was performed on stage III lung cancer patients (NSCLC), presenting locally advanced, non-operable tumor, invading local lymph nodes (IIIA: ipsilateral; IIIB: contralateral). Patients were given AE941 to platinum-based chemotherapy and radiation treatment. The primary objective is not just to reduce tumor size, but also to increase mean survival by 25% (from 13 to 16.5 months), a clinically significant and realistic increase for stage III NSCLC. One treatment group also received cisplatin and vinorelbine while the other group received carboplatin and paclitaxel. Each treatment group was given either a placebo or AE491. Exclusion criteria for this study included greater than 10-pound weight loss and eligibility for curative therapy.

The estimated number of patients for this study is between 700 and 800. The study is double-blinded and placebo-controlled, with standard patient follow-up, including regular exams and imaging studies.

The major toxicity reported from shark cartilage is nausea, which was quite manageable. Two other considerations in this study are: storage of specimens and drug, and competition posed by other groups for a limited patient population (stage III NSCLC).

Before it was eclipsed by chemotherapy, the use of proteolytic pancreatic enzymes (PPE) in the treatment of cancer were recognized by many practitioners and medicine journals. PPE given orally are known to be well absorbed in the gut, and may even undergo an enteric circulation similar to that of bile acids.

Many best cases of treatment of advanced cancer with PPE reveal dramatic improvement in otherwise fatal, rapidly advancing cancers. A modest retrospective study of patients treated by Dr. Kelly, a pioneer in the use of PPE to treat cancer, also showed improvements in patient survival.

In 1993, Dr. Gonzalez was invited to NCI to present his own best case series of 25 cases. One patient, called "Mort," presented with advanced, poorly differentiated, metastatic pancreatic cancer, considered fatal. (This interesting case will be written up by the publisher of Oncology News.) Eight years after diagnosis, Mort is still alive and his tumors are gone. Even though this case did not meet the criteria of the time, a 50% reduction in tumor mass lasting four weeks, the patient still clearly showed even greater improvement over a different time line.

In a small pilot study (appearing in the journal Cancer and Nutrition) Dr. Gonzalez treated 11 patients presenting with biopsy-proven, stage II-IV, inoperable cancer. The treatments began in 1994. As of the date of this conference, 9 lived one year, 5 lived two years, 4 lived three years and 2 are currently alive.

These pilot studies clearly call for further research. Proctor and Gamble contributed several million dollars initially, and then NCI took over the funding of the project.

The study evaluating Dr. Gonzalez’ regimen, a.k.a. PANCAM, (formally entitled "Evaluation of intensive pancreatic proteolytic enzyme therapy with ancillary nutritional support in the treatment of inoperable pancreatic adenocarcinoma") is a phase III randomized clinical trial. The purpose is to rigorously evaluate a therapy deemed by a pilot study to have potential benefits. Patients are to be randomized to receive either the Gonzalez’ regimen or standard, conventional treatment.

The study was carefully designed. Advice and guidance was duly sought from the appropriate communities, in an effort to ensure the results withstand scrutiny. Patients in the study have a median survival of six months, but are chosen based on their willingness to participate, comply, and continue with the study. The primary endpoint is survival and the secondary endpoints are tumor response and, notably, quality of life.

Many patients are resistant to randomization.

To refer patients or learn more about the trial, please call Dr. Gonzalez (Manhattan directory assistance) or the nurse coordinator, Michele Gabay is 212-305-9467.

Have you got many patients yet?

No. Fifty patients have been evaluated, three were willing to be randomized, but none of them met other eligibility criteria. Therefore we have no patients yet.

The treatment protocol and diet are standardized with some degree of variability.

Giving individualized treatment in a non-random fashion is more realistic than randomizing, but unfortunately, randomizing was necessary to maintain the validity and integrity of the study in the face of traditional criticism.

No. The trial is carried out in New York, but patients may participate from anywhere. If patients are randomized to receive the standard treatment, it can be administered by any local oncologist; patients randomized to receive the Gonzalez regimen can self-treat at home. The travel to New York to learn the therapy does not seem to be an impediment for any interested patient.

Forty to 50 per arm, that is 80 to 100 total.

Yes.

Most patients were using shark cartilage in adjuvant therapies.

During patient visits, patients will be asked what else they are taking, but a comprehensive data base may not be easy to develop.