|
|
|
|
A Personal Experience With a Targeted Chemotherapy Clinical Trial MLN2704 = hJ591 + DM1 = a humanized monoclonal antibody combined with a chemotherapy drug(DM1). The following is a report on my participation in a phase I clinical trial of MLN2704. MLN2704 is a humanized monoclonal antibody(hJ591) conjugated with(attached to) DM1(a chemotherapy drug). This is ‘targeted’ chemotherapy as the monoclonal antibody transports the DM1 to prostate cancer cells(targeting the prostate specific antigen membrane (PSMA) found on prostate cancer cell surfaces. Phase I trials are dose escalation to determine the maximum tolerated dose. I originally was going to get the 2nd dose in the series (51mg/m2), but ended up in about the middle of the dosing scheme (120mg/m2). As you can read below, it appears to be a ‘well tolerated’ drug on repeat dosing, but at the dose I received, not very effective in stopping the spread of my prostate cancer.
Background/History
November 2, 2002: I stopped DES as my psa had been rising since July 2002. I was going to start taking another drug, but before I started that I was told about a clinical trial - Phase I testing of MLN2704, a new drug, at MSKCC in NYC. I had to stop even more drugs I was taking in order to get into the trial. When tested on 12/10/02 at MSKCC for entering the trial, my liver enzymes were too high -- a new event for me as they had previously always been within normal -- some drug or combination of drugs must have caused the liver damage (elevated ALT and AST). Retesting a week later, locally, showed they were 'OK' so we again went to MSKCC on January 6, 2003 for re-screening. It was a devastating surprise to find AST/ALT still tested high -- the test we had done here had been invalid or at least was not indicative of what was really happening(apparently AST and ALT can bounce up and down.) I eventually stopped ALL medications and supplements except Lupron and Zometa, added silibinin(helps liver) and have prayed a lot. PSA didn't rise much in January, but at one point was doubling in 30 days. Finally, liver enzymes began to decrease. (they have to be less than or equal to 1.5x(upper limit of normal at MSKCC). 3/14/03. I now have 4 markers showing progression of the prostate cancer: alkaline phosphatase -- bone involvement; PAP -- metasatic disease increase; PSA and the positive CT Scan. My liver enzymes are close to acceptable, so we have an appointment at MSKCC on Monday 3/17/03 to re-do the trial screening. If I pass, I will start the trial on 3/24/03. I have been 'off treatment' for almost 5 months -- not a good thing to do -- so should not be surprised that the cancer has taken this opportunity to forge ahead. In the event I still do not get into this trial, I plan on starting on a weekly chemotherapy regimen -- with one of the taxanes, either as a single agent or in combination with some other drug. One of the problems with entering clinical trials is the requirement that you be off certain medications (or all 'treatment' medications) for specified lengths of time -- this is often not in the best interest of the patient as during that time the cancer can progress to the point that it becomes much more difficult to arrest continued growth. I'm on the edge on this one -- the far, to me, increasingly slippery edge. 3/19/03 We're back home after going through the screening process for the trial for the 3rd time -- this time I qualify for the trial and I am scheduled to receive the MLN2704 drug on Monday 3/24/03. The dose I will receive is 120mg/m2(square meters of body surface area). Additional doses are at approximately every 5th week (week 1 – dose, weeks 2,3,4 – monitor & rest; week 5 start a new cycle). On 3/17/03 PSA 59.59, PAP 33. I'll be the 6th lab rat (human lab rat) to get this drug(instead of the 2nd as would have originally been the case).
Background on this Clinical Trial Title: A Phase 1 Single Ascending Dose Trial of MLN2704 (DM1 conjugated monoclonal antibody MLN591) in Subjects with Metastatic Androgen Independent Prostate Cancer The Study Drug: MLN2704 is a humanized monoclonal antibody(hJ591) conjugated with DM1(a chemotherapy drug). This is ‘targeted’ chemotherapy as the MoAb targets PSMA (prostate specific membrane antigen) that is found on prostate cancer cells. Sponsor: Millennium Pharmaceuticals. (1); Study ID Numbers M59102-042. Purpose: This is the first study of MLN2704 administered to humans. The purpose of the study is to determine the highest dose of MLN2704 that can be given safely to patients with prostate cancer, and to identify any side effects associated with taking the drug. This study will also evaluate how MLN2704 is taken up (absorbed), broken down (metabolized) and eliminated (excreted) by the body. This process is called pharmacokinetic analysis. Study Protocol Schedule: Within 2-4 weeks of starting, screening is done to see if you qualify for the trial. This includes blood and urine tests and a CT and a bone scan(BS). Next, patients receive the study drug which is administered by IV over 2.5 hours. You are monitored that day for a total of 6 hours. That same week you return the next day, skip a day and then return for a final day. These are to draw blood and obtain urine samples for pharmacokinetic studies and also to evaluate you for any reactions to the drug. Subsequently, you return on each of 3 more weeks and then receive the second dose on the 5th week. This sequence is repeated at least one more time for a total of 3 doses. CT and BS are scheduled after 12 weeks on the trial. A later update of the protocol allowed repeat dosing beyond the initial 3. My Schedule and week-by-week Diary Here is my schedule of screening, drug administration and post-therapy observations: Screening – 3/17/03 and 3/18/03. Visit 1. Blood and urine samples drawn for PSA, PAP, liver function, kidney function, wbc, rbc, etc. Also a bone scan and CT scans. Assuming you are within the protocol set limits, a schedule of further visits is set up. Status: completed 3/17/2003 and 3/18/2003. PSA 59.95, ACP 4(<1.5), BS-, CT+. 1st Dose(120mg/m2, 6th dose level) – Monday 3/24/03 - Visit 2 -- week 1. Blood(CBC, chemistry, PSA, ACP) and urine samples are again taken and the MLN2704 drug given by infusion into a vein over about 2.5 hours. Visits this week are also on Tuesday and Thursday for observation, blood and urine samples and a physical(on Thursday). 1 week later – Monday 3/31/03. It has been a week since I was given the drug. Today, blood and urine samples are again taken. PSA 56.20 so the drug is doing something(down from 63.16 and ACP has dropped from 3.6 to 2.8! Hurrah! 4/9/03 – PSA 51.74 and ACP 2.9 so I am still responding. This turns out to be the nadir (low value) for these markers as on 4/14/03 and 4/21/03 they were both increasing steadily. Side effects observed after 1st dose. Physically, none. However, my liver enzymes (AST and ALT) increased significantly, but then decreased back to within the normal limits. Also my WBC (and ANC) counts decreased but they also increased sufficiently to enable the 2nd dose to be given. (WBC = white blood cell count, ANC = absolute neutrophil count). 4/21/03 – 2nd dose of MLN2704. PSA 54.92, ACP 3.9 – so I have lost most of the ground I gained after the 1st dose. This second dose goes well – no adverse reactions and we only have to be there 4 hours. Immediately after having the IV removed, we are able to head home and do not have to return until a week later. I hope this 2nd dose lasts longer and has more of an impact than the 1st dose did. 4/28/03 – one week after dose #2. Today, blood was drawn for evaluating CBC, complete metabolic panel, PSA and ACP as well as some blood for research use. No urine was needed for this visit. The next day I get the results and they show a drop in PSA from 54.92 to 50.72. The ACP dropped from 3.9 to 3.0. Once again, AST and ALT are elevated – maybe less than after the 1st dose and there appears to be a less severe impact on my WBC and ANC values. Another couple of weeks will see where these values all go. I’m hoping that the PSA drop is for longer than 2 weeks this time. 5/5/03 – Overall, not a good week. This is now two weeks after dose #2. Blood and urine drawn. PSA 47.32, ACP 4.0 – PSA down 3.4 (6.7%) but ACP up(33%). The bad news is that on the Saturday before this appointment I started to experience pain in my lower right back along with some intermittent nausea and dry vomit. Sunday and Monday I felt better and it wasn’t until we get the labs back from Monday showing an elevated BUN(blood urea nitrogen) (24) and serum creatinine (1.9) that some blockage of the right kidney was possibly the cause of the pain. An ultrasound of the kidneys, ureters and bladder was done that showed hydronephrosis in the right kidney and possible blockage of the ureter. The next day I had a CT scan, 1st without contrast which didn’t provide enough information and that was followed by full contrast CT. That CT showed that one of the lymph nodes that prostate cancer had invaded had continued to enlarge and was likely pushing on the ureter in such a way that flow of urine to the bladder was being blocked. This can lead to kidney failure and can be a very serious problem. A stent can be placed in the ureter to hold it open – for a while, but unless the metastases is controlled it will again close the ureter. This progression in the lymph nodes is not a good sign and may indicate the study drug isn’t being effective(yet) – or working fast enough to prevent further progression of the disease. Next, we consulted a local urologist who clarified my options. The stent in the urethral tube likely would work only a short time if the metastasis isn’t controlled. A tube could be inserted in the back, connecting to a bag to collect urine, thereby avoiding the ureter altogether or I could just let that kidney die and depend on only the one remaining kidney. The stent might be OK, if the tumor can be controlled, but the other two options have zero appeal. We basically didn't like what this urologist had to say. The ureteral stent would provide the least impact on my quality of life. I had a lot of pain, which was also added to by being constipated with a lot of gas buildup in the abdomen. Taking oxycodone (5mg) has tamed the pain. The 5/12/03 appointment at MSKCC will be an interesting one! 5/12/03. As I indicated above, this appointment would prove interesting. Basically, I was put into the hospital. PSA had increased from 47 to 80 in one week. Acid Phosphatase had dropped, however. The PSA 80 was reconfirmed on a subsequent re-test. So, instead of my PSA staying low or rising only slightly when compared to the behavior after the 1st dose, we now see a rapid progression. In the hospital, they put me on an IV with saline/dextrose (my source of food); x-rays confirm an Ileus(constipation and gas); ultrasound re-confirms the right kidney hydronephrosis. A long time has passed since my last bowel movement – the pain killers really have not helped this at all. Arrangements are made to have a ureteral stent placed on 5/13/03 by one of the MSKCC urologists. 5/13/03. This was MRI day and Stent day. More fun than a barrel of monkeys! The MRI required almost an hour in the tunnel. I wore headphones with ‘classical’ music to keep me company. The MRI showed that two lymph nodes are causing my kidney problems – identified as the right common and external iliac nodes – lymphadenopathy – sizes are 3.3x2.9 and 2.8x1.4. Next, off to the operating room for the stent. This is done under sedation. So, I slept through the procedure. Afterwards, I awoke in the recovery area and then they took me back to the hospital room. Normally, this can be done as an outpatient procedure, but since I was already in the hospital this worked out fine. I would have had to go back to our hotel for the night anyway. I experienced some burning on urinating – short term and had occasional pink urine(blood in the urine) for a week. Creatinine and BUN normalized(1.2 and 19 respectively). 5/19/03. Today, I was originally scheduled to receive dose #3. However, since my kidneys were ‘recovering’ this 3rd dose has been postponed. PSA 95.20 – again, a significant progression. Acid phosphatase has also increased. I’m seriously considering ending my participation in this trial and getting on standard chemotherapy. I have no pain at present, but do experience some fatigue and some shortness of breath. 5/28/03. Back at MSKCC. I always do a log-linear plot of my PSA and Acid Phosphatase. Once we arrive at the cancer center, they draw blood, but we don’t have the results until that evening or the next day, so we are always dealing with the results of a week earlier. Our travel distance(8 hour drive) precludes arriving early enough the day before to have the blood drawn (has to be before 11am for PSA and acid phosphatase.) Thus we have this discussion while looking at the graphs: Hmmmm, acid phosphatase appears to be trending downward(good) with a lot of noise, which we ignore. PSA rise is slowing down. Hmmm, maybe we can do a 3rd dose today. Well, that is what happened – the chemotherapy area said that they could take me that afternoon, so I was infused with a 3rd dose of MLN2704(same dose as the previous 2 – 120mg/m2). The infusion causes me no problems. Of course he next day, when we see the laboratory results, I am really worried as PSA is up again to 108.79 (but doubling time has lengthened out to 46 days(was 9 days and 18 days the previous two weeks). Acid phosphatase is now up to 3.6 – what it was when I started. This isn’t getting me anywhere. I’ll have a PSA and acid phosphatase, CBC and chemistry panel done again on 6/4 – maybe the 3rd dose will rekindle a decline in PSA. I hope, I hope. 6/4/03. Back at MSKCC. PSA 94.43 – down from the 108.79. This is a VERY modest decrease for which I am grateful, but a long, long way from <30 which would represent a >50% RR in PSA decrease. Acid phosphatase dropped to 2.9 so it is still bouncing around. I’ll get another PSA each of the next two weeks and a new Bone Scan and CT-Scans(the 12th week of the trial). That will either end the trial for me(progression? Stable disease? Responding?). Again, we will just have to wait and see. 6/16/03. Today is a see the doctor day, have blood drawn, get a chest x-ray, bone scan and a CT-scan. After returning home, I get word that I am officially off the MLN2704 trial, and in a couple of weeks I will probably start taxotere. The CT-Scan this time showed a new, nasty surprise in the form of a nonocclusive thrombus in the right proximal femoral venous system, i.e., up high enough in the thigh to be picked up by the scan. Thus I am busy getting anti-coagulated with first low molecular weight heparin and then back onto coumadin(I was on for 3 years straight, earlier). I'll get my INR up to the 2.0-2.5 range. This clot isn't blocking blood flow(yet). I have had my entire right leg swelling since March 1 – 1st off and on and now persistently and had had two whole leg ultrasound scans that were negative for blood clots. The only explanation I am aware of is lymphadema with the cancer a major factor in my lymph nodes on the right side. My right leg swelling has gotten worse in the last few weeks and this thrombus might now be a contributing factor. Hard to walk with the leg like it is. Also, the CT scan show progression relative to the 18 March(about 25% more measurable disease), so this new 'miracle' drug isn't much of a miracle for me – at least at the dose and treatment interval I got (120mg/m2, every 5 weeks.) Last PSA was 80, down from 95 but I started the trial with a PSA of 63. BS is ambiguous - might show progression or might be more 'degenerative changes'. Planar x-rays indicate possible mets in right sacrum and left iliac. We'll go to MSKCC on June 30 for a wrapup visit and get MSKCC's official input on another treatment(which chemotherapy). I’m a poor candidate to take emcyt with the blood clot, so single agent taxotere 25-30mg/m2 3 of 4 weeks is probably a good starting point. So this phase I trial, a calculated gamble, did provide a learning experience for me and should add to the database for drugs of this type. For myself, I’m moving on and we'll see what happens next. June 30, 2003. The wrapup visit. This was an underwhelming visit. PSA has increased from 80 to 86. We are given 3 choices for chemotherapy regimens that can be done locally. One is weekly taxotere with emcyt; another is just weekly taxotere and lastly high dose pulsed administration of calcitriol plus taxotere weekly. With the recent blood clot in the right thigh, emcyt isn’t a good idea at this time - although MSKCC indicated it would be OK if anti-coagulated and if there was no DVT extension of the thrombus.
References 1. Millennium Pharmaceuticals developmental drugs, www.mlnm.com/rd/oncology/candidates/mln2704.asp Also, go to www.clinicaltrials.gov and put in the Study ID Numbers M59102-042 to locate the trial information -- this includes eligibility requirements.
HH 7/20/03 |
|
This information is provided for educational
purposes only and does not replace or amend professional medical advice. Unless
otherwise stated and credited, the content of
www.hrpca.org is by and the
opinion of and copyright © 2001-2008 by H. Hansen. All Rights Reserved.
Our policy regarding privacy, right to reprint and contact information are
at About Us.
|