Background... I was diagnosed with CML in March of 1999. At Diagnosis my white blood count was 392,000 and I was in chronic stage. My cytogenetic test showed 20 out of 20 cells Ph+ or 100% Philadelphia chromosome positive. I took Hydrea for 4 months until July when I went to M. D. Anderson in Houston, Texas to see Doctor Moshe Talpaz. Dr. Talpaz was conducting clinical trials on Gleevec at the time but I did not qualify because the trial would only accept patients who had failed Interferon. Dr. Talpaz put me on a trial of Interferon, Ara-C and HHT. At the end of 3 months , my cytogenetics had improved slightly. I had 4 normal cells out of 20 or 80% Ph+. At 6 months I had lost my response and was back to 100% Ph+. I remained 100% Ph+ for the rest of the trial so in August of 2000, I qualified for and started the Gleevec trial. After 1 year on 400 mg of Gleevec daily, I was still at 100% Ph+ so Dr. Talpaz increased my dose of Gleevec to 600 mg. After 6 months on 600 mg my cytogenetics showed 2 good cells out of 20. My dose was increased to 800 mg and Neupogen was added to counteract low absolute neutrophil counts. My next cytogenetics at 4 months showed 11 good cells out of 20 or 45% Ph+. I was finally going in the right direction, but the good news was short lived. My next cytogenetics showed that I had lost ground and was 70% Ph+. The next cytogenetics was 90% and finally I was back at 100%. Over the last year my counts have been slowly creeping up. My WBC had been running in the 2s and 3s in the fall of 2002. In November of 2002 it was in the 5s. In April of 2003 when I started the HSP70 trial at the University of Connecticut it was in the 7s and rose to the 11s during that 3 month trial and finally in August 2003 was 23.1. At that point I added hydrea to the 800 mg of Gleevec and knocked WBC count back into the 8s. My last BMB on October 22 showed me to still be in chronic phase with 100% Ph+.

Thursday…Shela Broussard, Dr. Talpaz’s research nurse called me and asked if I would still like to participate in the Phase I trial of the New Bristol-Myers Squibb drug designated BMS-354825. I have been hearing of this new drug for about a year and I know that Dr. Talpaz and Dr. Sawyers at U.C.L.A. are very excited about it. I have heard that it is 1000 times more powerful than Gleevec in the lab and that it has killed all resistant forms of CML cells. The question is, “How toxic is it”. Well, I know how toxic CML is so I agreed to join the study. I will be in the first group (cohort) of 3 patients to get the drug. I will have to live in Houston for at least 3 months and spend a lot of time at the clinic. Shela tells me she is working on the details and will call me back when she gets everything worked out. I had a bone marrow asparation on October 21st but the protocol calls for a bone marrow biopsy (Bone chip removed in addition to marrow). She said that she is trying to get a one time exemption for me so I will not have to have another bone marrow draw done. I will not bore you with the details, but at this point I had one week to get an apartment and move to Houston. My wonderful wife of 31 years miraculously had found me an apartment 1 mile from the medical center and had put a hold on it within 24 hours.

Wednesday…Shela called and said to be in Houston on Monday, November 10, 2003 to begin tests in preparation for the trial. She said that I would actually get the first dose of BMS-354825 on Thursday, November 13, 2003. My wife Karen and I will spend the next few days moving me to my new apartment and getting enough furniture into it so that it is livable. This is no small task.

Monday…I reported to the clinic today for Eligibility assessment, medical history, physical exam, assessment of performance status, baseline signs and symptoms, vital signs and urinalysis. I was given the informed consent document to read and sign. This is a legal document which is mostly routine and boring however, here are some of the interesting parts.

Purpose of study: The goal of this clinical research study is to test the safety of BMS-354825 in patients who are resistant to treatment with Gleevec. Researchers will try to find the highest dose of BMS-354825 that can be safely given to patients without causing severe or life-threatening side effects. Another goal is to see what effects (good or bad) it has on patients and their cancer. Researchers will also study the activity and level of BMS-354825 in your blood.

Possible BMS-354825 side effects: Low white blood count, low red blood count, low platelets, diarrhea, bloody diarrhea, ulcers, bleeding in the stomach and intestines, nausea, vomiting, heart problems including bleeding in the heart muscle, damage to the heart muscle, changes in the electrical activity of the heart that can lead to serious irregular heart rhythms and cause palpitations and loss of consciousness. There may be bleeding in the lining of your mouth, your skin (easy bruising) or other body parts. It may cause abnormal liver function tests, allergic reactions, bone changes, loss of appetite, muscle and joint aches, fatigue or weakness, fever, and changes in kidney function. BMS-354825 may also cause chromosomal damage.

Patients should not become pregnant or father children while on the study.

BMS-354825 may or may not help patients.

The above statements are not inclusive and some are paraphrased by me for brevity.

By the way…I had to stop Hydrea as well as all supplements, vitamins etc. today. I stopped Gleevec on October 30th the first day Shela called.

Tuesday…I reported to the clinic for a chest x-ray, SGOT, BHCG, Troponin I, Troponin T (Heart enzymes), CK/ CK-MB, CD4+ T Cell Count, Fish (blood), CBC, DIFF, PLT, PT, PTT, INR. Between all this and 7 extra tubes of blood for research, I think it was about 17 tubes total but I lost count. I saw Dr. Talpaz for a few minutes in the afternoon. He asked me if I had any questions and he wished me luck.

Wednesday…They call this “Day minus 1”, the day before you get the drug. I got to the clinic at 7:30 am. They put me in a bed for the day of tests. Tests included ECGs (Electrocardiograms) every hour except the last two which were two hours apart (7 total ECGs). Blood draws every 30 minutes for first several hours then every hour. I think that the total was 17 tubes of blood. They did put in an IV so they didn’t have to stick me so much. Thankfully, the drug company accepted the previous bone marrow aspiration done two and a half weeks ago so I didn’t have to do that again. I left the clinic at 5:20 pm. This was a long day, I am tired.

Thursday…Day 1: I arrived at the clinic at 7:30 am again for another day in the bed with ECGs every hour and blood draws every 30 minutes. At 9:05 Dr. Talpaz came in and gave me my first dose of BMS354825. It is 3 small white tablets each 5 mg for a total of 15 mg once a day. I take it for 5 days and stop it for 2 days. Then repeat the cycle. I am not to eat or drink anything but water for at least 2 hours before and two hours after taking the drug. I asked Dr. Talpaz why do we break from the drug for 2 days every week. He said something to the effect that it is always done that way in the beginning and that Gleevec started the same way. I suspect it has something to do with the drug company wanting to measure clearance times and half life etc. The rest of the day went the same as the day before, 7 ECGs and about 20 tubes of blood more or less. My WBC today is 10.0, Hgb 14.6, PLTs 274. Got out at 5:20 pm no side effects so far.

Friday…Day 2: I got to the clinic at 7:30 I had a PK (Pharmakinetics) blood draw and ECG at 9:00 am. At 9:05 I took my second 15 mg dose. Still no side effects.

I saw Doctor Talpaz at about 2:00 pm. I will be seeing him once a week for the duration of my stay here. He gave me another prescription for the drug.

Here is my biggest concern. This trial does not allow any other drugs to control my counts other than Agrylin for high platelets. The starting dose is surely sub-therapeutic. For example Gleevec Phase I started at 25 mg per day. As we all know 300-400 mg has been established as the minimum therapeutic dose. The 15 mg of drug I am taking is unlikely to effect my counts much. The question is, how fast will my counts rise? Dr. Talpaz says if the WBC reaches 100,000 he can do Leukapheresis on me. I am not happy about that. I hope the drug company will realize that most of the patients likely to come into this study right now will need something to control their counts while working up to an effective dose.

From this point forward, I will only post to this diary on days when I have news that might interest some of you.

Monday…Day 5: Still no side effects. I feel good. I got to the clinic at 7:30 am for another marathon day. Numerous blood draws about 19 I think. ECGs every hour and out at 5:20 pm again. Today’s WBC 8.8, Hgb 14.3, Plts 238. No, the BMS drug is not reducing my counts. This is still the Hydrea which peeks in 7 to 10 days after you take it. I have been off it 8 days.

Tuesday…Day 6: I will not be taking the drug today or tomorrow. This my first 2 day break. I got to the clinic at 8:30 am for a ECG and PK blood draw. I feel very good.