8

Selection of Subjects

8.1

Subject Inclusion Criteria

8.2

Subject Exclusion

1. Current enrollment in another clinical trial.
2. Pregnant or breast feeding women. With the exception of post-menopausal or infertile women, a negative blood test for pregnancy is mandatory before entry on study. Fertile persons refusing to use contraceptives may not participate.
3. Known human immunodeficiency virus (HIV) positivity or acquired immune deficiency syndrome (AIDS)- related illness.
4. Currently active second malignancy, other than non-melanoma skin cancers. Patients with other malignancies must have been disease free for 5 or more years.
5. Mental incapacitation or psychiatric illness that would prevent the patient from giving informed consent.
6. Other severe concurrent disease which, in the judgement of the investigator, would make the patient inappropriate for entry into this study.

9

Study Drugs

9.1

Tetrathiomolybdate

9.2

N-acetylcysteine (NAC)-Rx Mucomyst or generic equivalent

9.3

Ascorbic Acid Tablets - OTC

9.4

Zinc Sulfate (or Zinc Acetate)

10

Clinical Efficacy Assessments: Objective Tumor Response

10.1

Methods of Assessment

The principle evaluation of antitumor activity will be based on serial objective determination of changes in measurable lesion size. The newly developed World Heath Organization Response Evaluation Criteria in Solid Tumors (RECIST) will be employed.

Radiographic evaluation is preferred to evaluation by clinical examination. Tumor assessments should preferably include abdominal CT scans with contrast. Abdominal MRI scans are acceptable. Conventional CT and MRI should be performed with cuts of 1.0cm or less in slice thickness contiguously. Spiral CT should be performed using a 0.5cm contiguous reconstruction algorithm. Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable for assessment of chest lesions. Chest CT scans or chest X-rays should be followed in patients with known pulmonary metastases at baseline or in whom pulmonary symptoms develop during treatment.

Documentation by color photography including a ruler is necessary to estimate the size of skin lesions. Ultrasound is a possible alternative to clinical measurements for superficial palpable nodes, subcutaneous lesions, and thyroid nodules. Ultrasound may also be used to confirm the complete disappearance of superficial lesions usually assessed by clinical examination. Ultrasound should not be used to measure tumor lesions that are clinically not easily accessible. Endoscopy, laparoscopy, and radionuclide scan should not be used for response assessment.

The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. To ensure compatibility, the baseline x-rays/scans to assess response must be performed using identical techniques. Copies of the scans must be available for review.

Malignant tumor masses (target lesions) should be selected on the basis of their size and their suitability for accurate repetitive measurements. All patients must have at least one target lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) greater than or equal to 2.0cm with conventional radiographic techniques or MRI, or greater than or equal to 1.0cm with spiral CT scan. To assess objective response, it is necessary to estimate the overall tumor burden at baseline and use this as a comparator for subsequent measurements. Whenever possible, several measurable lesions up to a maximum of 10 target lesions representative of involved organs should be identified, measured and recorded at baseline. To allow later retrieval, lesions should be clearly marked on the films or otherwise identified. If the lesion is detected by more than one method at baseline, the investigator should select at baseline the method to be used at subsequent evaluations. All measurements should be performed using a caliper or ruler and should be recorded in metric notation in centimeters. A sum of the longest diameter for all target lesions will be calculated and reported as the baseline sum longest diameter. The baseline sum longest diameters will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease by repeated assessment of the sum of the longest diameters during treatment.

All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Measurements are not required and these lesions should be followed as "present" or "absent".

All baseline evaluations should be performed as closely as possible to the treatment start and never more than 14 days before the beginning of the treatment. After randomization, oncologic assessment will be repeated every 6 weeks, for patients in both treatment arms.

    10.2 Definitions of Objective Tumor Response and Progression-Imaging

Measurable lesions are defined as malignant tumor masses that can be accurately measured in at least one dimension (longest diameter to be recorded) as greater than or at 2.0cm with conventional techniques or as greater than or equal to 1.0cm with spiral CT scan. Clinical lesions will only be considered measurable when they are superficial (e.g. skin nodules, palpable lymph nodes).

Nonmeasurable lesions are defined as malignant tumor masses that cannot be accurately quantified for tumor response, and would include bone lesions, leptomeningeal disease, ascites, pleural or pericardial effusions, lymphangitis of the skin or lung, abdominal masses that are not confirmed and followed by imaging techniques, cystic lesions, irradiated lesions, and disease documented by indirect evidence only (e.g. by laboratory tests such as alkaline phosphatase.)

10.2.1 Target Lesions

Complete response (CR) is defined as the disappearance of all target lesions.

Partial response (PR) is defined as a greater than or equal to 30% decrease in the sum of the longest dimensions of the target lesions taking as reference the baseline sum longest dimensions.

Progressive disease (PD) id defined as a greater than or equal to 20% increase in the sum of the longest dimensions of the target lesions as reference the smallest sum of the longest dimensions recorded since the treatment started, or the appearance of one or more new lesions.

Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum of the longest dimensions since the treatment started.

10.2.2 Non-Target Lesions

Complete response (CR) is defined as the disappearance of all nontarget lesions.

Non-Complete Response ((Non-CR)/Non-Progressive disease (Non-PD) is defined as a persistence of one or more nontarget lesions.

Progressive disease (PD) is defined as unequivocal progression of existing nontarget lesions, or the appearance of one or more new lesions.

Patients will be defined as Not Evaluable for Response (NE) if there is no post-randomization oncologic assessment.

All patients who have a reduction in tumor lesions sufficient to meet criteria for CR or PR on at least one occasion will be considered to have objective evidence of response. To be considered a confirmed objective response, these same criteria for response must be confirmed with a follow-up scan obtained greater than or equal to 4 weeks from the scan documenting the response.

The reasons for discontinuation of treatment without objective evidence of disease progression must be reported on the Study Termination CRF. If a patient is removed from therapy for any reason other than radiographic evidence of tumor progression, every ----- should be made to radiographically document disease progression even after discontinuation of treatment.

10.2.3

Evaluation of Overall Objective Tumor Response

10.3

Methods of Assessment- Tumor Markers

11

Clinical Safety Assessments

11.1 Definition of an Adverse Event

An adverse event is any untoward medical occurrence in a patient or trial subject administered a drug or biologic (medicinal product) or using a medical device; the event does not necessarily have a causal relationship with that treatment or usage.

Adverse events include the following:

• All suspected medication adverse reactions
• All reactions from medication overdose, abuse, withdrawal, sensitivity or toxicity
• Apparently unrelated illnesses, including the worsening of a preexisting illness
• Injury or accidents. Note that if a medical condition is known to have caused the injury or accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the accident (fall) should be reported as two separate events. The outcome of the accident (e.g., hip fracture secondary to fall) should be recorded under Comments.
• Abnormalities in physiological testing or physical examination (findings that require clinical intervention or further investigation beyond ordering a repeat [confirmatory] test).
• Laboratory abnormalities that require clinical intervention or further investigation (beyond ordering a repeat [confirmatory] test) unless they are associated with an already reported clinical event. Laboratory abnormalities associated with a clinical event (e.g., elevated liver enzymes in a patient with jaundice) should be described under Comments on the report of the clinical event rather than listed as a separate adverse event.

11.2 Serious Adverse Events

A Serious Adverse Event is an untoward medical occurrence, regardless of whether or not it is considered related to the study medication, which results in:

• Death, while on treatment or less than or equal to 30 days after last study drug administration, including deaths due to disease progression.
• Deaths occurring greater than 30 days following the last dose need not be reported as serious adverse events unless they are a result of an event that started while on treatment or less than or equal to 30 days of the last dose.
• In addition, any death that occurs greater than 30 days following the last dose that the investigator assesses as possibly related to the study medication must be reported as a serious adverse event.
• A life-threatening adverse event (e.g., the patient was at immediate risk of death from the event as it occurred). It does not include an event that, had it occurred in a more serious form, might have caused death.
• In-patient hospitalization or prolongation of existing hospitalization (excluding hospitalizations for administration of the study drug or procedures required by the study protocol or tumor-related diagnostic procedures or other planned hospitalization).
• Treatments in the emergency room for procedures such as hydration that do not require admitting the patient to the hospital are not considered serious.
• Persistent or significant disability/incapacity
• Congenital anomaly/birth defect
• Any other adverse event that the investigator judges to be serious or which is defined as serious by the Regulatory Agency in the local Country. Medical judgement should be exercised in deciding whether a reaction is serious in other situations. Important adverse reactions that are not immediately life-threatening or do not result in death or hospitalization but may jeopardize the patient should be considered serious.
• An event needs not be reported as a serious adverse event if it exclusively represents a relapse or an expected change or progression of the baseline malignant disease. This type of event needs only to be reported as an adverse event.
• Deaths due to progressive pancreatic cancer that occur greater than 30 days following the last dose of study medication do not need to be reported as a serious adverse event.

11.3 Unexpected Adverse Events

Unexpected adverse events are defined as those events that were not previously reported with study drug as referenced in the protocol, investigator's brochure, consent form, or package insert or which are symptomatically and pathophysiologically related to a known toxicity but differ because of greater severity or specificity.

11.4 Adverse Event Reporting Period

The adverse event reporting period for this trial begins upon receiving the first dose of study medication and ends 30 days after termination of study medication.

All adverse events that occur in trial subjects during the adverse event reporting period specified in the protocol must be reported to P&U, whether or not the event is considered medication related.

In addition, any known untoward event that occurs subsequent to the adverse event reporting period that the investigator assesses as possibly related to the study medications should also be reported as an adverse event.

11.5 Eliciting Adverse Event Information

The investigator is to report all directly observed adverse events and all adverse events spontaneously reported by the trial subject. In addition, each trial subject will be questioned about adverse events at each clinic visit following initiation of treatment. The question asked should be, "Since your last clinic visit have you had any health problems?", or a similar type of open-ended query.

11.6 Reporting Requirements

Reporting Requirements for Adverse Events

11.7 Recording Adverse Events in the CRF's Procedures

Data on all adverse events (serious and non-serious, expected and unexpected, related or not related) will be collected in the CRF's. Minimum requirements of adverse event data to be recorded are type of event, start and stop dates, highest severity grade, seriousness, action taken, outcome and relatedness to either study medication or tumor.

· Symptoms or Signs Associated with Chemotherapy, Radiotherapy or Concomitant Medications

Symptoms or signs associated with administration of chemotherapy, radiotherapy, or concomitant should be reported as adverse events.

· Symptoms of Neoplastic disease

Symptoms of pancreatic cancer are not to be considered adverse events in this trial, provided that they are present at baseline (before treatment with study medication is initiated) and that they do not worsen during the treatment. In cases where an increase in severity occurs, the event should be reported in the appropriate section of the CRF.

· Abnormalities in Physiological Testing or Physical Examination

Grading of Adverse Events

Note the distinction between the gravity and the intensity of an adverse event. Severe is a measure of intensity; thus, a severe reaction is not necessarily a serious reaction. For example, a headache may be severe in intensity, but would not be classified as serious unless it met one of the criteria for serious events listed above.

11.8 Exposure In Utero

If any trial subject becomes or is found to be pregnant while receiving a study medication or within 3 months of discontinuing study medication, the investigator is to submit an adverse CRF that includes the anticipated date of birth or pregnancy termination. The subject is then to be followed by the investigator until completion of the pregnancy. If the pregnancy ends for any reason before the anticipated date provided, the investigator should notify the P&U monitor.

If the outcome of the pregnancy meets the criteria for immediate classification as a serious medical event (i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an aborted fetus]), the investigator should follow the procedures for reporting serious medical events; i.e., report the event to the principal monitor by telephone and follow up by submission of appropriate adverse event CRF's.

Note that "spontaneous abortion" includes miscarriage and missed abortion.

All neonatal deaths that occur within one month of birth should be reported, without regard to causality, as serious adverse events. In addition, any infant death after one month that the investigator assesses as possibly related to the in utero exposure to the study medication should also be reported.

In the case of a live birth, the "normality" of the newborn can be assessed at birth (i.e., there is no required minimum follow-up of a presumably normal infant before the Exposure in Utero form can be completed).

The "normality" of an aborted fetus can be assessed by gross visual inspection unless there are pre-abortion laboratory findings suggestive of a congenital anomaly.

12

STATISTICAL CONSIDERATIONS

12.1

Survival

Survival is defined as the time from date of randomization to date of death. In the absence of confirmation of death, survival time will be censored at the last date of follow-up.

12.2

Objective Tumor Response Rate

Objective response rate is defined as the proportion of patients who have any evidence of objective CR or PR.

Confirmed objective response rate is defined as the proportion of patients who have evidence of objective CR or PR that is confirmed by follow-up tumor assessment greater than or equal to 4 weeks from the tumor assessment documenting the initial response.

12.3

Time to Objective Tumor Response

Time to response is defined as the time from date of randomization to first objective documentation of response.

12.4

Duration of Objective Tumor Response

Duration of response is defined as the date of first objective documentation of response until the first objective documentation of tumor progression or death due to tumor progression in the absence of previous documentation of tumor progression. For patients with responding tumors who do not have objective evidence of tumor progression and who are removed from study, who die of causes not related to pancreatic cancer, or who are given antitumor treatment other than the study treatment, duration of response will be censored. Patients who die of unknown causes will be considered to have experienced tumor progression.

12.5

Time to Objective Tumor Progression

Time to objective tumor progression is defined as the time from date of randomization to first objective documentation of tumor progression or death due to tumor progression in the absence of previous documentation of tumor progression. For patients who do not have objective evidence of tumor progression and who are removed from study, who die of causes not related to pancreatic cancer, or who are given antitumor treatment other than the study treatment, time to tumor progression will be censored. Patients who die of unknown causes will be considered to have experienced tumor progression. A CA19-9 increase meeting criteria for tumor marker progression does not constitute adequate objective evidence of tumor progression. However, such a CA 19-9 increase should prompt a repeat radiographic evaluation to document whether or not objective tumor progression has occurred.

12.6

Time to Treatment Failure

Time to treatment failure is defined as the time from date of randomization to first objective documentation of tumor progression, or off-treatment date, or death, whichever comes first. Patients who are still on treatment at the time of the analysis and patients who are removed from therapy by their physicians during an objective response and who, at the off-treatment date, have no evidence of objective tumor progression will not be considered to have experienced treatment failure, unless the withdrawal is due to the occurrence of a medical event. For these patients, time to treatment failure will be censored at the off-study date. Censoring for time to treatment failure will also be performed in those patients who are given antitumor treatment other than the study treatment before the first objective tumor progression, off-study date, or death. A CA19-9 increase meeting criteria for tumor marker progression does not constitute adequate objective evidence of treatment failure. However, such a CA19-9 increase should prompt a repeat radiographic evaluation to document whether or not objective tumor progression (and thus treatment failure) has occurred.

12.7

Clinical Benefit

Time to first definitive performance status worsening is the time from randomization until the last time the performance status was no worse than at baseline.

Time to first definitive weight loss is defined as the time from randomization until the last time the percent weight decrease from the baseline was less than 5%.

Time to first albumin decline is defined in terms of the time from randomization until decline in albumin by 10%, by 20%, and by 40% below baseline (based on central laboratory data).

12.8

Treatment Administration

All treatments are given orally at 20 mg gel capsule dosage for TM and 300m mg each ascorbic acid/N-acetylcysteine for antioxidant treatment. Initial dosages are six TM capsules and three antioxidant capsules per day, respectively. These are given regardless of weight or age. The cerauloplasm levels will determine if the TM dosage is changed over time as judged by the physician.

12.9

Study Population

The as-treated population consists of all patients who actually receive study drug (at least one injection), with treatment assignments designated according to actual study treatment received.

The primary endpoint of survival will be assessed in the as-randomized and the as-treated patient populations.

No placebo groups will be in this study.

13

QUALITY CONTROL AND QUALITY ASSURANCE

An investigators meeting will be held prior to the initiation of the study at which the investigators and site coordinators will be informed regarding details of the protocol, medication supplies, and monitoring responsibilities. The CRF's will be explained in detail.

Each clinical site conducting this study has agreed to conduct this study according to GCP standards and in conformity with local and national requirements (e.g., FDA or ICH standards). Monitoring visits to the trial site will be made periodically during the trial to ensure that all aspects of the protocol are followed. Source documents will be reviewed for verification of agreement with data on the CRF's. Original patient records (e.g., hospital charts, clinic records, laboratory printouts) should be available at each study site for source document review by a P&U monitor. Source document review is the cross-checking of information recorded on study CRF's with that recorded in the original patient records. It is recognized that for observations and evaluations conducted solely for the purposes of the study, the CRF may be the original patient record. It is not the purpose of source document review to ensure that all information on CRF's is also recorded elsewhere in the patient's records; the purpose is to help ensure that the CRF's accurately reflect information generated during the study.

The investigator/institution must guarantee access to source documents by appropriate regulatory agencies. The trial site may also be subject to quality assurance audits by P&U as well as inspection by appropriate regulatory agencies. It is important that the investigators and their relevant personnel are available during the monitoring visits and possible audits and that sufficient time is devoted to the process.

14

Ethical Conduct of the Trial

The trial will be performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964 and later revisions.

15

Institutional Review Board/Independent Ethics Committee

It is the responsibility of the investigator to obtain approval of the trial protocol/amendments from the IRB/IEC. All correspondence with the IRB/IEC should be filed by the investigator.

The study will not be started until approval of the protocol, the patient information and the informed consent form has been obtained from the appropriate IRB/IEC. It is the responsibility of the investigator to forward a copy of the written approval and a list of the members, their titles or occupation, and their institutional affiliations, to P&U. The approval should include study identification and the date of review.

Protocol amendments are to be submitted to the IRB/IEC (and other local authorities, according to local regulations) prior to implementation.

The investigator will make required progress reports to the IRB/IEC, as well as report any serious adverse events, life-threatening problems or deaths. The investigator will also inform the IRB/IEC of reports of serious adverse events (provided to him/her by the sponsor) occurring in other clinical studies conducted with the study drug. The IRB/IEC must be informed by the investigator of the termination of the study.

The investigator should file all correspondence with the IRB/IEC.

The study will not be started until written approval receipt acknowledgment or elapse of the statutory waiting period from the approved IRB committee.

16

Patient Informed Consent

16.1

General Information

It is the responsibility of the investigator to give each patient (or the patient's acceptable representative) prior to inclusion in the trial, full and adequate verbal and written information regarding the objective and procedures of the trial and the possible risks involved. The patients must be informed about their right to withdraw from the trial at any time. Refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and will not prejudice further medical treatment. Written patent information as contained in the Sample Informed Consent (Appendix D) must be given to each patient before enrollment. Furthermore, it is the responsibility of the investigator to obtain signed informed consent from all patients prior to inclusion in the trial.

The responsible physician will inform the patient about the background and present knowledge of the drug under study and will give the patient pertinent information as to the intended purpose, possible benefits, and possible adverse experiences. The procedures and possible hazards to which the patient will be exposed will be explained.

An explanation of whom to contact for answers to pertinent questions about the research and research subject's rights, and who to contact in case of research-related injury will be given.

Written patient information, when indicated, must be given to each patient before enrollment.

If during the study the patient refuses to continue taking part in the study, the investigator will respect this and the patient will receive optimal and appropriate care.

The signed informed consent forms should be filed by the investigator. Where confidentiality laws preclude this, they should not be made available, but filed for possible future audits. The investigator will confirm the receipt of informed consent from each patient by completing and signing the appropriate CRF.

The patient information and the informed consent form to be used must be approved by the same IRB/IEC approving the conduct of this study.

The patient should also be informed that the data will be stored and analyzed by computer in a national database at cancerprotocol.com, that country-specific regulations for the handling of computerized data will be followed and described in the patient information and that identification of individual patient data will only be possible for the investigator. Furthermore, the patients should be informed about the possibility of inspection of relevant parts of the hospital records by health authorities.

16.2

US-Specific IRB/IEC Requirements

This protocol and the consent form that will be used must be approved by an IRB/IEC before the study is initiated. The IRB/IEC must comply with current FDA regulations. Other investigator responsibilities relative to the IRB/IEC include the following:

• Submission of any advertisements to recruit study subjects to the IRB/IEC for review and approval
• During the conduct of the study, submission of progress reports to the IRB/IEC as required, and securing re-review and approval of the study at least once per year
• Reporting immediately to the IRB/IEC any unexpected serious adverse event that occurs during the study
• Reporting information to the IRB/IEC if P&U provides notification about serious adverse events reported in other studies using these study medications
• As required, obtaining approval from the IRB/IEC for protocol amendments and for revisions to the consent form or subject recruitment advertisements
• Providing the IRB/IEC with any other information it requests before or during the conduct of the study
• Maintaining a file of study-related information that includes all correspondence with the IRB/IEC
• Notifying the IRB/IEC when the study is completed
• After study completion, providing the IRB/IEC with a final report on the study
• A statement that the study involves research
• Purpose of the research
• A description of procedures to be followed and identification of any that are experimental
• Expected duration of the subject's involvement in the study
• Reasonably foreseeable risks or discomforts associated with participation in the study
• Benefits the subject may reasonably expect from participation in the study, including the amount and timing of any payments for study participation
• Alternate treatment or courses of treatment, if any, that may be advantageous to the subject
• A statement that participation is voluntary and that if the subject chooses not to participate or withdraws from the study, he or she will not lose any benefits he or she would otherwise have
• Whom to contact if the subject has additional questions about the study. (Provide both name and telephone number)
• Whom to contact if the subject has questions about subject's rights. (Provide both name and telephone number)
• Whom to contact about an injury associated with the study. (Provide both name and telephone number)
• A statement that described the extent to which confidentiality will be maintained for records that identify the subject and that notes the possibility that FDA and P&U representatives may inspect the study records
• A compensation statement indicating any available payment for treatment related injury
• When appropriate, additional information relating to:
  • unforeseen risks
  • additional costs to the subject
  • how new findings on the experimental treatment will be reported to the subject
  • the number of subjects in the study or who have previously received the experimental treatment
  • the possibility of terminating the subject's participation in the study without warning
  • consequences of a subject's decision to withdraw from the study
  • procedures for orderly termination of study participation
  • identification of restrictions or inconveniences (e.g., restrictions on smoking or use of alcohol or over-the-counter medications, the need to avoid pregnancy, performance of pregnancy tests or drug screens, etc.)

The language in the informed consent must be understandable and in no way coercive.

17

References

PATIENT INFORMATION AND INFORMED CONSENT FORM

I, _________________________, do hereby consent to participate in a research study for cancer. This study has been explained to me and I fully understand the following:

A. PURPOSE

To determine if anti angiogenesis treatment with copper reduction therapy and antioxidant therapy will reduce tumor load.

B. PROCEDURES

Tetrathiomolybdate (TM) will bind copper and remove it from the body. Copper reduction is a broad- band method to reverse angiogenesis. Ascorbic acid- N-acelylcysteine are potent antioxidates that work synergistically. These have an effective anti-tumor activity.

C. TREATMENT

Start 20mg TM at six times/day, once with each meal and three times between meals. Two weeks into the TM treatment, the antioxidant treatments begins with one capsule every six hours.

D. DURATION OF THERAPY

Therapy will continue until cerauloplasin is 20% of baseline value or 8.0 mg/dL. TM dosage may be capsules to maintain the 20% baseline level for 90 more days to allow the blood vessels feeding the tumor to die. If my disease is stable or shrinking and there is no other reason to stop the drug therapy. Treatment will continue and be evaluated every 60-90 days by the physician.

I understand the antioxidant treatment will continue until my physician judges it should stop.

When my participation in the study is to be terminated, I will complete one last questionnaire, have blood drawn, and undergo assessment of my tumor response to therapy.

If conditions occur which would make my participation detrimental to my health, my doctor may discontinue this treatment even though I might wish to proceed with further therapy. In addition, the entire study may be terminated, at the discretion of the sponsor, if unacceptable risks or side effects develop. In the event of either of these occurrences, my doctor will review my individual treatment options.

My doctor(s) would like to be able to track my cancer after the treatment phase of the study and would also like to keep me informed of any new information regarding the treatment I received while on this clinical study. Therefore, during the first year I will be contacted monthly and during the second year every 3 months by the study nurse and asked about my cancer.

E. POSSIBLE DISCOMFORTS AND/OR RISKS:

Cancer treatments often have side effects. The treatments used in this study may cause all, some or none of the side effects listed in this document. In addition, there is always the risk of very uncommon or previously unknown side effects occurring. Although very unusual, it is even possible that side effects from chemotherapy may result in death. My doctor will be checking me closely to see if any of these side effects are occurring. Routine tests will be done to monitor the effects of treatment. Side effects usually disappear after the treatment is stopped. In the meantime, my doctor may prescribe medication to keep these side effects under control. I understand, I may need to be hospitalized in order for my doctor to treat the side effects.

The effects of chemotherapy on the human fetus are known to be harmful from animal studies. If I am pregnant or nursing, I will not be allowed to participate in this study. If I agree to participate in this study, and am of childbearing potential, I must not become pregnant. If applicable, the initial blood tests may include a pregnancy test. I can avoid pregnancy by using an appropriate method of contraception (e.g., an IUD, partner having had a vasectomy, oral contraceptives, abstinence, or being surgically sterile). If I should become pregnant while participating in this study, I must inform my doctor immediately and my treatment options will be discussed with me. If I am male, I must be either sterile or use an approved contraceptive method (e.g. condom).

· Possible Side Effects: Anemia

Under no circumstances should the cerauloplasmin drop below 8.0 mcg/dL. Ceruloplasmin increases. Lower dosages of TM will be given as judged by the physician

· Prevention/Treatment of Side Effects:

F. POSSIBLE BENEFITS

Suspension of TM treatment until minimal values of ceruloplasmin in are determined.

It is not possible to predict whether or not any personal benefit will result from the use of the treatment program. Possible benefits are reduction in my disease and prolongation of my life.

G. ALTERNATIVE METHODS

Alternative treatments that could be considered in my case include chemotherapy, radiation therapy, or other experimental therapy. I may also choose to have no further therapy and receive supportive care only. This may result in continued growth of my disease. I understand that my doctor will want to discuss these alternatives with me.

H. NEW INFORMATION FOR THE PATIENT

I understand that any new information that is developed during the course of this study that may influence my willingness to continue participation in this study will be made available to me.

I. PATIENT CONTACTS

Dr. ___________________; phone _________________ has agreed to answer any inquires that I may have concerning the procedures and has informed me that I may also discuss with him/her this concerning this research study and my right as a research subject.

J. PATIENT CONFIDENTIALITY

I understand that my clinical trial information will be recorded on forms and sent to the clinical trial sponsor. The data on the forms will be entered into an electronic database for storage and statistical analysis. By signing the informed consent form I authorize this access to my records. All records in which my name appears will be kept confidential. My identity will not be revealed on any forms, or in any report or publication.