Category Archives: LDK378

Back on LDK378

First, the good news. On Monday my liver enzymes had fallen to the acceptable range and I went back on LDK378 at 400mg. As long as I am on this particular therapy, I will stay away from alcohol, levaquin and NSAID’s (advil had been my anti inflammatory of choice). I have been eating lots of liver loving foods (beets, beets and more beets) as well as a daily dose of prunes and bran: my friend Mateo suggested All Bran Buds, which I am happy to say are highly effective.

For the time being, ice cream has been added to my diet, and I have already gained back four of the pounds I lost. Happily, my wheezing is much improved and my energy is back in spades.

Perhaps best of all, my spirits have risen accordingly; I am back in fighting mode.

 

 

Playing the numbers

Slow, but steady. The results are in from my recent CT scan and 40% resolution has eased on up to 45%. A significant five percent, as the negative side effects (gastrointestinal issues) from LDK378 have increased in intensity as well.  Dr. Shaw and I had spoken about possibly moving my dose back down to 400 mg if there had been no incremental improvement in tumor burden.

The Radiology Report is less cheering, although certainly is not what I would characterize as a bad report. It reads:

IMPRESSION:  Persistent groundglass opacities in the anterior and inferior left lung and along the right minor fissure. The opacities in the left lung are slightly more prominent. There are no definite new lesions.

It’s all a curious algorithm; this response/non-response thing. “Tumor size has traditionally been estimated from bidimensional measurements (the product of the longest diameter and its longest perpendicular diameter for each tumor)” (quoted from an article in the Japanese Journal of Clinical Oncology) Basically, a linear measurement, which is quite dependent upon the outside diameter of a lesion, is used to estimate volume. Baseline measurements are taken at the onset of a particular treatment, and response (and/or stability or progression) is assessed by comparing successive scans to the initial chest CT. Evidently my earlier 40% (https://lifeandbreath.wordpress.com/2011/12/14/big-four-oh/) was not the cutoff for partial response but rather exceeded it. I should have done my homework. From Wikipedia:

Evaluation of target lesions

  • Complete Response (CR): Disappearance of all target lesions
  • Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD
  • Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
  • Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesion

Odd as well is the 5% increase in response coupled with the possible area of greater consolidation noted on the radiology report. Which to me illustrates the limitations of any sort of quantitative measurements; it is all seems a bit hypothetical/ best guess sort of stuff. Data collection. Bottom line, my lungs feel and sound pretty darn good.

The numbers on my labs are closer to normal as well; the oral iron supplement I began taking several weeks ago is helping.

The one concern of the moment is my liver enzymes, transaminases-SGOT and SGPT.

So what is a transaminase? From MedicineNet.com: The transaminases are enzymes that catalyze chemical reactions in the body in which an amino group is transferred from a donor molecule to a recipient molecule. (!)

SGOT is an acronym for serum glutamic oxaloacetic transaminase and SGPT for serum glutamic pyruvic transaminase. Just in case you wanted to know. What is really relevant is that they are enzymes in the liver and elevated values of either can be an indicator of liver inflammation.

My SGOT/SGPT values were ever so slightly elevated the entire time I was on crizotinib. When I went off treatment they fell to normal levels, but soon after my first dose of LDK378, the levels again became slightly elevated. After my dose went up to 500 mg, the values began to rise again.  My SGOT level peaked at 84 a week ago and is now down to 67. The normal reference range for SGOT is 9-32 U/L  (units per liter of serum–the liquid part of blood). My SGPT was at 79 last week and this week  topped out at 102. Normal reference ranges for SGPT are 7-30 U/L.

Hopefully the SGPT has peaked and will start to go down. In the meantime, a glass of wine in the evening is not an option. Sadly, we’ve been invited to a wine tasting party this very weekend (for the oenophiles out there, all with a rating of 93 or above). When I asked Alice (Dr Shaw) if I’d be able to participate, she said, “Wine tasting is just sips of wine, right?” “Well…” I replied, “it can be done that way”.  So I’ve been given clearance to slosh a bit around in my mouth. Just like the real sommeliers. I don’t believe I’ll be able to bring myself to spit it out though; that just wouldn’t be right.

Big four oh!

I had my second chest CT scan since starting on LDK378 a little over a week ago. The report from the radiologist was basically ‘stable’, But at a scan review with Dr. Shaw, there was clearly visual evidence of further improvement (lessening density of the ground glass opacities). The trial review board at Novartis must think so as well, because several days later Alice emailed to say I was now at the 40% mark, which is the cut off for a partial response. It’s not as clean in there as it was after I started crizotinib (Xalkori), at least not yet. But we’re working on it.

September of 2008/pre-crizotinib

November 2008/post-crizotinib

For comparison, here are the before and after images of my lungs in 2008. The left lung is actually on the right of each individual image. It is smaller than the right lung, because the entire lower lobe was removed in 2005, at the time of my diagnosis. Before I started the PF-03241066 trial (crizotinib, Xalkori), the remaining upper lobe of my left lung was getting pretty filled up with cancer, and you can see some activity starting in the right lung as well; particularly near the top.

August 2011/pre-LDK378

The image above is from a photograph I took of my chest CT scan as displayed on a computer monitor, so it’s not as clear as it could be. I’ve not included the two scans I’ve had since I started the trial, as I’m not certain if I am allowed to do that yet (as a subject now, not a patient, the rules are not the same). I’ve included this image simply to give you an idea of how much cancer had come back. Not as diffuse as in 2008, but well on the way and really rather dense in the bottom of the remaining upper left lobe.

So, what I can’t show you, but can tell you, is that the most recent scan is significantly clearer (and if you are considering percentages, 40% certainly sounds twice as good as the initial 19% resolution). I’m no longer coughing and my lungs feel fine.

This trial is in the dose escalation phase, and I entered at 250 mg. Per protocol, once the subjects at the next higher dose had gone without adverse events for two cycles (a cycle is three weeks long), I would be allowed to go up to that dose, or 500 mg. Last monday was my first day at the stronger dose. I’m hoping stronger=more effective yet.

So all in all I’m feeling well. Occasional bouts of diarrhea would seem to be a side effect, and I’ve become mildly anemic, which leaves me a bit rundown and intolerant to cold (not quite as rosy as I once was either). It would seem to be a mixed etiology of nutritional anemia and anemia of chronic disease, according to my labs (and my oncologist!). My hematocrit is 31.2 (normal reference range 36-46), my hemoglobin is 9.6 (normal reference range 12-16) and my MCV (mean cell volume) is 72 (normal reference range 80-100). My iron level is 18 (normal range 30-160) and ferritin is 6 (normal range 10-200).

In a subsequent post I will  go into greater detail about anemia (I’ve been reading up on it, and it’s rather fascinating).

So that’s the medical update. I’m off to eat some spinach.

Viewing the actual scans

I had my appointment with Alice (Dr. Shaw) on Monday, and we were able to view the images of the before and after scans together. They do indeed appear much improved. In my left lung, there remains a hazy footprint of what was formerly an area of consolidation. It could represent inflammation or, possibly more likely, unresolved cancer. The right lung (my ‘good’ lung), looks almost entirely clear.

It is important to remember at this point that A. we are in the dose escalation phase for LDK378, and the therapeutic dose may not have been reached yet, and B. this is not my first exposure to an ALK inhibitor and my cancer had acquired resistance to crizotinib (Xalkori).

All in all–a very respectable response. We will be watching my next set of scans closely and also positioning for dose escalation as soon as possible (there are certain constraints per protocol–and it will be six weeks or so before escalation is a feasibility). Update–Alice received the measurements for resolution (which is factored in a way that is very reliant on degree changes in borders of tumor rather than density) and it is 19%. This is a good place to remind all that I learned a long time ago not to be defined by numbers. I prefer qualitative to quantitative analysis, and symptomatically, I am much improved.

Life goes on. I’ve been busy adding to my portfolio of fallen leaves, although it has not been a stellar season for leaf peeping. They take the fall colors quite seriously in these parts, and there was a story on the front page of the local paper detailing the factors behind the disappointing showing. A very wet spring, coal tar spot, hurricane Irene (which atomized so much salt, it was found on the leaves of maples twenty miles inland). I believe myself to be rather adept at finding something beautiful under any circumstance though, so here goes:

YES! The results of the latest scan are in

I have been feeling well for the past week. My cough has resolved, my energy is up and the chills are gone. All good signs.

This past Monday I underwent the bronchoscopy. Quite uneventful aside from the nasty numbing stuff they squirt up your nose and down your throat prior to the exam. “This is going to feel like you’re drowning” counseled the attending nurse with no apparent irony. And it did.

On Thursday I was back in Boston for my chest CT scan. Although I’d been given a bye on barium for the past two years of the crizotinib trial, I am once again required to drink two ‘milkshakes’. As I’ve explained in some previous detail, I am oblivious to most of the discomforts involved in my day to day medical care. You don’t even want to know how many times I get jabbed with a needle. However, I have never liked putting something in my mouth that I don’t want there. I am, in fact, almost phobic in this regard. Oral contrast is tough for me, and hopefully I can once again talk upper management out of the necessity of such an (onerous) detail.

I had taken the bus in, and David picked me up at the hospital after my exam and we continued on to Randolph, where my oncologist, Dr. Alice Shaw, was being honored by the American Lung Association. Also in attendance were three of Alice’s other patients, including Chris and his wife Karen, pictured on the rather dramatic staircase of the venue. They have an adorable daughter who is just two, and Chris has done quite well on crizotinib. I wish him many more years of success.

Chris and Karen

Bright and early yesterday morning, Alice called and said she had reviewed the scans and that they looked really good, and as well the bronchoscopy was completely negative for any findings. Some hours later she forwarded the CT report, which frankly sounds even more positive than what I’d expected from her description. It reads:

FINDINGS:

Lines/tubes: None. Lungs and Airways: There is improved consolidation in the left upper lobe and lingula with residual ground-glass opacities, which had been previously chronic and progressive and are considerably improved from 8/31/2011, consistent with improvement in lymphangitic carcinomatosis.

There is a stable 3-mm nodule along the minor fissure. The surrounding smaller nodules have resolved. Pleura: There is a stable small left pleural effusion.

Heart and mediastinum: The thyroid gland is normal. No significant mediastinal, hilar or axillary lymphadenopathy is seen. The heart and pericardium are within normal limits. There is mild pericardial thickening, which appears more prominent compared to 8/31/2011.

IMPRESSION:

History of non-small cell lung cancer status post left lower lobectomy. Improvement in lymphangitic tumor spread in the left lung. Stable indeterminate 3-mm nodule along the minor fissure. Slightly increased mild pericardial thickening.

I like how many times improved or a variation thereof is used in the first paragraph (three), and the addition of considerably is even better. Stable appears twice in the second paragraph. And in IMPRESSIONS, the key words are improvement, stable, and slightly increased. This is a very good, considerably improved, report. Yippee!

And now for some definitions of less than familiar terms:

lymphangitic carcinomatosis:  A condition in which cancer cells spread from the original (primary) tumor and invade lymph vessels (thin tubes that carry lymph and white blood cells through the body’s lymph system).

This is the definition from the National Cancer Institutes online dictionary. From Medscape reference we get this explanation:  The lungs are one of the most common targets for metastatic disease.  Most pulmonary metastases are nodular, but a significant minority is interstitial. Lymphangitic carcinomatosis (LC) refers to the diffuse infiltration and obstruction of pulmonary parenchymal lymphatic channels by tumor.

Interpretation? I believe it is simply another way to describe metastatic lung cancer.

I also looked up the significance off mild pericardial thickening (the pericardium is the membranous sac enclosing the heart), and will discuss it with Alice before I attempt to interpret this finding.

Bottom line; it is a very good report. I have to wonder if I really did have an infection that the latest course of levaquin vanquished. Whatever the underlying cause of my initial malaise as well as the less than stellar PET scan, it is now evident that the LDK378 is having it’s way with my cancer. I’m tripping over myself with gratitude, and well, excitement. The personal impact is obvious, but I’m focusing on the big picture as well; perhaps LDK378 will prove to be yet another viable treatment option for those who harbor an ALK mutation. That would be really be something.

Let’s ride

Ok. So. About that LDK378 trial…The gallery above is from my first day two weeks ago. Please note the woodchuck.  And Sarah, giving me the high five after my lead-in dose.  And how tired David looks; it was a very long day. Long enough that I had time to wander the halls, peruse the Wall of Hope and hang out in the lovely Healing Garden. Long enough that it was barely light when we left the house and quite dark when we returned home.

I’m going to directly lift from the Research Consent Form (a many paged document that you must read and sign prior to enrollment in a trial) to describe the specifics of day one:

PK run-in period (3days) in Part 1 of the study 

Pharmacokinetics (PK) is the study of the actions of a drug in the body over a period of time (eg, how it is absorbed, distributed, broken down, and excreted).

The PK run-in is a 3 day period (before you begin daily study treatment with LDK378) where you will be given a single dose of LDK378 and then have repeated blood tests to see how your body handles the drug. (The tests are called pharmacokinetics or PK tests.) About 1/3 teaspoon of blood with be drawn at each PK blood draw.

  • Day one of PK run-in:  You will have blood drawn, take one dose of LDK378, and then have blood drawn 7 more times with the 8 hours after taking LDK378.
  • Procedures performed on Day 1 of the PK run-in:
  • Physical examination
  • Vital signs
  • In addition, blood pressure and heart rate will be measured before every PK blood sample is drawn.
  • 3 consecutive  EKGS after the single dose of LDK378 and another EKG 4 hours after the dose of LDK378.
  • Additional blood for research blood test to measure biomarkers and the amount of circulating tumor cells in your blood (about 4 teaspoons). Biomarkers are substances such as proteins that may give information about how LDK378 is affecting your body.

So that is the technical run-down. In reality, it all felt rather festive.  Just as my t-shirt proclaimed, this wasn’t my first rodeo and I kind of knew what to expect. 

Not long after the first dose, I experienced some cramping and Irene performed anti-diarrhea acupuncture. That was it for drama; no other discernible side effects. 

Wouldn’t it be wonderful if my personal history of lung cancer treatments someday represented the paradigm; thus far, they have only gotten easier and become more effective.

Consider: almost immediately following my diagnosis in 2005, I endured a rather brutal lower left lobectomy. That was followed by four grueling sessions of cisplatin and taxotere. In 2008 I spent two months taking tarceva with all of the side effects and none of the benefits.

And then came crizotinib (now Xalkori). Not only were the side effects minimal, it stamped out the cancer raging in my lungs and kept it at a low smolder for almost three years.

Will the LDK378 do the same? I am hopeful. The day after my lead-in dose, I was able to walk to the top of a steep hill without stopping numerous times to catch my breath; something I’d not been able to do for some time now. I felt great.

And then, I started to feel crappy again. Which is part of why I haven’t written yet.

However, before any conclusions are leapt to, I need to add that there were several extenuating circumstances. Two weeks before my lead-in dose, I had been on a ten day course of levaquin for a sinus infection. It was the first time I’d had antibiotics in months, and a curious thing happened.

The cough and accompanying rattle in my lungs, which had persisted almost since my bout with the flu, disappeared. I had assumed both symptoms were due to the progression of my lung cancer and was actually quite startled when they cleared up.

My lead-in dose was on a Wednesday, and I didn’t have another dose (the start of continual dosing) until the following Monday. In the meantime, the feeling of low level crappy returned; aches, chills, fatigue and a cough. What the hey!

Several months ago I found an imbedded deer tick but in subsequent days did not develop a bullseye rash. However, just to rule out lymes disease as a potential cause of my current symptoms, I was tested. In addition, my circulating hormone levels and thyroid were checked; all three were normal. Alice (Dr. Shaw) called on Sunday to see how I was feeling and mentioned that the pre trial PET scan had shown more uptake in my lungs than she had anticipated.We discussed the possibility of a smoldering low level pneumonia, as areas of inflammation can light up a PET scan and be confused with cancer. Finally, yesterday I saw the ENT to rule out a lingering sinus infection. My nasal passages were clear, but we decided it might be smart to go back on another ten days of levaquin and see what happens.

So here’s hoping. The side effects from the LDK378 would seem to be non-existent. If the antibiotics do their magic, perhaps I can really get back in the saddle again. I am so ready.