At last, a “Gleevec” of our own?
If you follow general interest medical news, or if you know anyone who was diagnosed with CML, you would have heard of “Gleevec” (imatinib). This kinase inhibitor has revolutionized the standard of care for chronic myeloid leukemia patients. Gleevec is a potent inhibitor of the activity of a tyrosine kinase called “bcr-abl” (as well as a few other tyrosine kinases). It has demonstrated significant activity in patients with CML in all phases of the disease, whether they have received prior therapy or not. Since Gleevec therapy became well established, the annual mortality for CML patients has been reduced significantly (less than 2%-3% per year).
I wish I had a dollar for every time I dreamed wistfully for a “Gleevec” of our own. For a change, it seems I was not day-dreaming. The era of kinase inhibitor drugs for CLL is dawning and it looks to be a bright day. Since nothing in life or cancer therapy is ever simple, I think it is important for you to learn about kinases, how they work, what makes them so important. I will make the science as simple as I can, I promise it won’t hurt even a teeny bit.
Kinases – master controllers
Kinases are extremely important enzymes that control much of how the cells in our body function. There are several hundred different kinases, controlling different functions. One type of kinases, called protein kinases, are the largest group. Protein kinases can transfer a phosphate group from ATP to a protein in a cell, thereby activating the protein.
If that bit of chemistry began glazing over your eyes, try this for size. Kinases function as an “on” or “off” switches. Without the help of a particular kinase turning the protein “on”, the protein in question is inactive and cannot do the job it is supposed to do. Thus, kinases control much of the machinery of the cell – its ability to proliferate (have babies), move about the body, ability to receive or send messages to its neighbors, whether it lives or dies.
To put in blunt terms, kinases are the central master switches of how each cell in our body works. As you can imagine, all hell breaks loose if one of the master switch goes awry, if it gets stuck in the “ON” position too long for example. Mutations, deletions or mangling of the structure of a regulatory kinase can play havoc with the particular protein and the cell function it is supposed to control. Most if not all human cancers are thought to be caused by one or more malfunctioning kinases.
Kinases make nice targets for new drug development
So, if a malfunctioning kinase is at the root of a particular cancer, how about blocking that kinase and thereby block its bad influence on the proteins it is supposed to control? Great idea, but not that easy to do in real terms. Many kinases share common features. So, a drug that is developed to block a particular kinase may also block a bunch of other perfectly normal kinases, and thereby disrupt some vital function of the body. Broad spectrum kinase inhibitors can be very toxic because they can block too many vital pathways – a case of the cure being worse than the disease.
Even Gleevec, the miracle kinase inhibitor drug for CML, has some toxicity concerns. A 2006 article linked Gleevec to heart failure in a small percentage of patients. “Ten CML patients treated with Gleevec at the M.D. Anderson Cancer Center in Houston developed congestive heart failure, although they had normal heart function when they began taking the drug. Studies in mice and in culture showed that the Abl tyrosine kinase protects cardiac cells from damage; when it is inhibited, heart cells die”. This was a bit of an “unanticipated side effect”, according to the researchers.
I am pointing this out not to take away anything from the game changing ability of Gleevec. It has truly been a miracle drug that paved the way for better and more targeted drugs in its wake. But all too many times I get letters from our members upset with the slow pace of clinical trials, unable to see the point of all these careful protocols and detailed research. Why can’t the FDA just approve CAL-101, and get done with it? After all, it is a biologic drug and not a nasty chemotherapy drug, it can’t possibly hurt – can it? The answer is YES, IT CAN. Biologic drugs can hurt, can even kill. This is one of the reasons why early stage studies generally recruit late stage patients, people who have been through several layers of therapy already, so called “salvage-cases” with few good choices left. “Do no harm” is a very important oath to remember, if you are a clinical researcher and you wish to avoid unnecessary tragedies.
Do we have similar kinase targets in CLL?
Turns out, we do. Not just one target, but four of them. And all four kinase targets are being examined, with suitable small molecule inhibitors that may be able to stop them cold.
Unlike CML, which has a particular messed-up protein (as you would expect, the protein controlled by Bcr-Abl kinase is called Bcr-ABL protein) that is responsible for the cancer, CLL does not have any one single such protein.
But in the last few years we have learned a great deal about what makes CLL tick. We know for example, that much of the survival advantage of CLL cells lies in their ability to resist suicide signals from the rest of the body. This ability to ‘live long and prosper’ is hugely enhanced when the CLL cells are surrounded by their closest friends and relatives, so called “nurse-like cells” in their immediate microenvironment, constantly giving them encouraging feedback.
We know by now that just about any therapy can bring down CLL counts in the blood. Shrinking swollen nodes and clearing infiltrated bone marrow – that is a lot harder. This is because out in the open blood circulation CLL cells are not all that hard to kill. But once they are nicely tucked away in the bone marrow, swollen lymph nodes, spleen, liver etc, they are much harder to kill. Think of this as a criminal out in the open streets with no friends and no place to hide, scared out of his wits and with no one to give him a pep talk. Compare this poor sucker with a hardened terrorist with a lot of local supporters willing to protect him and hide him, defend him with their very lives. The guy with no friends is more apt to be panic stricken, make mistakes that lead to his capture and execution. Not so the guy well hidden with lots of local moral support.
The four kinases listed above are known to be over abundant in CLL cells, cooperating with the microenvironment. They magnify the survival and proliferation and maturation signals the CLL cells receive from their neighboring nurse-like cells, through the B-cell receptors that each B-cell has on its surface. If we can take away this constant and soothing pep-talk magnified by overactive kinases listed above, it becomes a lot easier to kill the CLL cells.
This is a distinctly different approach to killing CLL cells than the usual chemotherapy drugs we have come to love and admire (Not!). We are not trying to poison the CLL cells, we are only trying to kick their damn legs out from under them. And when they are down and floundering around out in the open, if they are not already dead because of their scary isolation from their fan club, that is when we can kill them easily with appropriate therapy. Here is a link to a recent editorial in “Blood” by Dr. Varsha Gandhi that does a better job of explaining the science than my cartoon version.
For a change we have an embarrassment of riches, four different kinase targets to try and block. The BTK (Bruton Tyrosine Kinase) and PI3K kinase are in the lead. The small molecule drugs that we hope will block these two kinases respectively are PCI-32766 and CAL-101. I will focus on CAL-101 in this article, since I have read the most about it. Down the road it will be the turn of PCI-32766. Let us hope that one of these days they will come up with more sexy names for these potentially life saving drugs.
The kinase that is targeted by CAL-101 is called PI3K. Biological systems are always complex, and there are four different forms of PI3K kinase with slightly different functions. These four brothers are called Alpha, Beta, Gamma and Delta – respectively. Why is this important, why don’t we hit the whole dang family of PI3K kinases while we are about it? Well, that would be like shooting ourselves in the foot. Brother Alpha and Beta are expressed on a wide variety of cell types, they control a lot of rather crucial functions. Block these two guys and the daily business of the body comes to a screeching halt. At the very least the toxicity levels will be very high, at worst the patient may die. The youngest two brothers, Gamma and Delta, are only expressed on white blood cells. Gamma deals mostly with T-cells and neutrophils. Delta is our guy, the one we have to stop dead in his tracks. PI3K-Delta is specific for B-cell proliferation, survival and maturation. And PI3K-delta is heavily over-expressed in CLL cells. What makes CAL-101 unique from all the other PI3K inhibitors is that it specifically inhibits this particular member of the PI3K family, the Delta form of it.
CAL-101 Phase I Study
This study is being done to see if the drug is safe, if it actually works the way we want it to, and decide what would be a safe standard dosage. There were 54 CLL patients in this trial (along with a bunch of NHL, Mantle Cell and Multiple Myeloma patients). All were heavily pre-treated patients, not a chemo virgin in the lot. Every single one had been exposed to fludarabine. Most also had Rituxan and alkylating agents such as cyclophosphamide. 81% had bulky nodes, fully third of them had the dreaded 17p deletion. I would call this a tough crowd to treat, your classic “salvage” cases.
CAL-101 is an orally available drug, meaning you can just pop the pill. Dosages went all the way from 50mg twice a day to 350mg once a day. Therapy continued on a daily basis as long as patients got benefit from it.
There was some toxicity: 24% of patients had grade 3-4 pneumonia (grade 3-4 is heavy duty stuff, as you know by now) and there was also grade 3-4 neutropenia in 24% of patients. Was this due to CAL-101 or was it due to the fact that this crowd was so heavily pretreated already, with most chemotherapy drugs known to man? The researcher believe there were no clear pattern of CAL-101 related symptomatic adverse events.
Now for the interesting stuff. It seems CAL-101 is very good at cutting the apron strings that keep CLL cells close to home, nicely tucked away in lymph nodes and bone marrow. CAL-101 shrank swollen nodes in all CLL patients in the study, even those with high risk 17p deletion. As the CLL cells got flushed out of the nodes and into open blood circulation, there was a huge spike in the white blood counts – but this was temporary as these CLL cells were soon killed. As much as 80% of the patients had their lymph nodes reduce by 50%. That is pretty impressive, especially in this relapsed and refractory group of patients.
For patients who went into the clinical trial with low platelet counts, presumably due to the infiltrative late stage CLL we discussed in an earlier article, there was significant improvement in their platelet numbers as the therapy proceeded. My guess would be this parallels gradual clearing out of the bone marrow, allowing new platelet formation.
Based on the dose response at different levels the researchers concluded that future studies will use 150mg / twice daily as the standard dose.
Here is the best part of the whole shebang: control over CLL was pretty durable. More than 48 weeks of follow-up and we have more than 50% of the patients are still going strong, in progression free survival. Generally speaking, SLL folks with bulky nodes are harder to treat than CLL folks. That was not the case here, CAL-101 works great with bulky nodes. And the bit that impressed me most is that the shrinkage of swollen nodes happened quite nicely even in patients with the high risk 17p deletion.
Here is a link to the PowerPoint presentation that the researchers made at the ASH2010 conference. It has the latest information on the clinical trial. I expect the abstract below had been submitted earlier to ASH, some of the data is not quite as up to date.
CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3 Kinase P110δ, Demonstrates Clinical Activity and Pharmacodynamic Effects In Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia
Oral Session: CLL – Therapy, excluding Transplantation: Novel Agents and New Approaches
Richard R. Furman, MD1, John C. Byrd, MD2, Jennifer R Brown, MD, PhD3, Steven E. Coutre, MD4, Don M Benson Jr., MD5, Nina D. Wagner-Johnston6, Ian W. Flinn, MD, PhD7, Brad S. Kahl, MD8, Stephen E. Spurgeon, MD9, Brian Lannutti, PhD10, Neil A. Giese, Ph.D.10*, Heather K Webb, Ph.D.11*, Roger G Ulrich, Ph.D.10, Sissy Peterman12*, Leanne M. Holes10* and Albert S Yu, MD10*
Introduction: The class I phosphatidylinositol 3-kinases (PI3Ks) regulate cellular functions relevant to oncogenesis. Expression of the PI3K p110δ isoform (PI3Kδ) is restricted to cells of hematopoietic origin where it plays a key role in B cell proliferation and survival. In chronic lymphocytic leukemia (CLL) the PI3K pathway is constitutively activated and dependent on PI3Kδ. CAL-101 is an isoform-selective inhibitor of PI3Kδ (EC50 of 62 nM in a whole-blood assay with >200-fold selectivity relative to other PI3K isoforms) that inhibits PI3K signaling and induces apoptosis of CLL cells in vitro.
Methods and Patients: This Phase 1 study evaluated the safety, pharmacokinetics, pharmacodynamics and clinical activity of CAL-101 in patients with relapsed or refractory hematologic malignancies. Sequential cohorts of patients were enrolled at progressively higher dose levels with cohort expansion based on toxicity profile and plasma exposure. CAL-101 was administered orally one or 2 times per day (QD or BID) continuously for 28-day cycles for up to 12 cycles (with the potential for more prolonged therapy on an extension protocol thereafter). Clinical response was evaluated according to standard criteria.
Results: At data cutoff, the study had enrolled 37 patients with CLL. Patients included: males/females n=31 (84%)/6 (16%) with median age of 65 [range 37 82] years, refractory/relapsed disease n=24 (65%)/13 (35%), bulky disease n= 29 (81%), and adverse cytogenetics of del(17p), del(11q) or both n=22 (63%). The median number of prior therapies was 5 [range 2-14]. The number (%) of patients with specific prior therapies included: rituximab n=37 (100%), purine analog n=37 (100%), alkylating agent n= 31 (84%), and alemtuzumab n=12 (32%). CAL-101 dose levels were 50 mg BID (n=1), 100 mg BID (n=4), 150 mg BID (n=11), 200 mg BID (n=10), 350 mg BID (n=7) and 300 mg QD (n=4). The median number of treatment cycles was 9 [range 1-13], with 21 (57%) patients continuing on treatment (11 on study and 10 on the extension protocol after 12 cycles). Symptomatic adverse events were infrequent, usually low-grade, and not clearly CAL 101 related. Grade ≥3 pneumonias occurred in 9 (24%) patients. Grade ≥3 hematological laboratory abnormalities included neutropenia n=9 (24%), thrombocytopenia n=4 (11%) and anemia n=3 (8%) that were not usually considered CAL 101-related. A pharmacokinetic analysis of dose-proportionality showed minimal increases in plasma Cmax and AUC at CAL 101 doses >150 mg BID; these data, taken together with the tumor regression results, have proved helpful in supporting Phase 2-3 dose selection. Flow cytometry of CLL cells from patients showed that CAL-101 reduced constitutive expression of phospho AKT to background levels when measured after 1 week of treatment (p<0.0001), demonstrating pharmacodynamic inhibition of activated PI3K signaling. Plasma concentrations of chemokines CCL3, CCL4, and CXCL13 were elevated at baseline and decreased significantly within 1 cycle of CAL-101 administration (p<0.001 for all comparisons). CAL 101 reduced lymphadenopathy in all 32 (100%) patients with at least 1 post-treatment tumor assessment; 29/32 (91%) achieved a lymph node response (≥50% reduction in target nodal lesions). An initial increase in peripheral absolute lymphocyte counts of >50% from baseline was observed in 21/35 (60%) patients; increases were maximal during the first 2 cycles and decreased thereafter; the pattern suggested drug-mediated lymphocyte redistribution. Considering nodal and peripheral blood changes together, partial responses were observed in 11/33 (33%) of patients. The median duration of response had not been reached; 7 patients had response durations of ≥6 months. Of 20 patients with CLL-related thrombocytopenia (baseline platelet counts <100,000/µL), 15 (75%) had either an improvement to >100,000/µL or a >50% increase from baseline.
Conclusions: CAL-101, an oral PI3Kδ isoform-selective inhibitor, shows acceptable toxicity, positive pharmacodynamic effects, and favorable clinical activity in heavily pretreated patients with CLL, including patients with refractory disease, bulky lymphadenopathy, and poor-prognosis cytogenetics. The high level of lymph node regression and prolonged duration of symptomatic tumor control strongly support evaluation of CAL 101 alone and in combination with other chemo/immunotherapy approaches to CLL management.
Disclosures: Byrd: Calistoga Pharmaceuticals: Consultancy, Equity Ownership. Brown: Calistoga: Consultancy. Kahl:Calistoga Pharmaceuticals: Consultancy, Research Funding. Lannutti: Calistoga Pharmaceutical Inc.: Employment. Giese:Calistoga Pharmaceuticals: Equity Ownership. Webb: Calistoga Pharmaceuticals: Employment. Ulrich: Calistoga Pharmaceuticals: Employment, Equity Ownership. Peterman: Calistoga Pharmaceuticals: Employment. Holes: Calistoga Pharmaceuticals: Employment. Yu: Calistoga Pharmaceuticals: Employment, Equity Ownership.
On-going Clinical Trials
The clinicaltrials.gov site lists four clinical trials for CAL-101 that are open and recruiting CLL/SLL patients. Each of the four trials listed below are live links, just click on them to see the full details.
- Dose Escalation Study of CAL-101 in Select Relapsed or Refractory Hematologic Malignancies
- An Extension Study for Patients Who Are Deriving Benefit With CAL-101 to Continue on Treatment at the End of the Current Study
- A Study of CAL-101 and Rituximab in Elderly Patients With Untreated CLL or SLL
- Study to Investigate CAL-101 in Combination With Bendamustine and CD20 mAb in Patients With Relapsed or Refractory Indolent B-cell Non-Hodgkin’s Lymphoma or Chronic Lymphocytic Leukemia
Trials 1 above is what we discussed above, the Phase -I trial for heavily pretreated patients. Trial 2 is continuation of that trial which allows patients to continue on the drug as long as they are getting benefit from it.
Trial 3 is for previously untreated but elderly patients. They plan to recruit 60 patients and one of the inclusion criteria is that volunteers have to be older than 65. I doubt most people consider 65 as “elderly” any more, but there you have it. The idea here is to see if in this “older” group of patients who still have their chemo naive status CAL-101 can deliver higher response rates along with low toxicity and remission durability – that is the Holy Grail combination. Remember, the Phase-I trial discussed above saw only 33% responses, and even those were only partial responses. I for one will be keeping my fingers crossed for the success of this trial with less refractory patients.
Someone asked me if the inclusion criteria are likely to be bent to let in patients who are close to 65, but not quite there yet. I doubt it. Clinical trial protocols are carefully developed with a lot of oversight by ethics committees etc. Playing fast and loose with inclusion criteria can get researchers into trouble and runs the risk of invalidating the hard won results. So, even if you got into every bar in town with fake IDs when you were not quite of legal drinking age, I doubt that would work to get you into this trial if you are not 65. Be patient. All of us get older each and every single day.
Trial 4 is once again for previously treated patients. But here the twist is that they will be combining CAL-101 with bendamustine and either Rituxan or ofatumumab. In other words, this is CAL-101 along with standard chemoimmunotherapy combination. I have no doubt that down the road someone will also want to do CAL-101 + FCR. The idea in these combination trials is to see if we can do better by bringing more fire-power to the game. What makes it interesting here is that we can hope CAL-101 drives out all the sneaky CLL cells luring in bone marrow and lymph nodes, while the big guns bendamustine and Rituxan wait out in the peripheral blood to kill the little buggers as they are flushed out. Good concept, it remains to be seen how the toxicity works out with this combination and whether it is more than paid for by stellar response statistics.
Is there any downside risk to CAL-101?
Aha. That is the million dollar question. As I pointed out in the earlier section of Gleevec, there can be “unanticipated adverse effects” with any drug, even kinase inhibitors. We can only hope to know what they are as we gain experience with this new drug through carefully conducted clinical trials. 24% grade 3-4 pneumonia and 24% grade 3-4 neutropenia seen in the Phase -I trial we discussed above gives me some cause for concern. The researchers felt this did not have anything to do with CAL-101, it was just a case of the patients recruited for the trial being really heavily pre-treated already and therefore prone to any little thing going around.
I did a little digging around. I found a few abstracts that raised questions for me. If I understood these articles correctly, drugs such as CAL-101 may interfere with the maturation and proper function of NK-cells and T-cells. Does this imply long term (maintenance protocols) use of CAL-101 may cause sufficient dysfunction in NK cells and T-cells – which in turn may increase aggressiveness of infections and secondary cancers? Did this have anything to do with the 24% of patients in the Phase-I trial getting grade 3-4 pneumonia?
I will be the first admit, I do not know exactly how important these studies are, especially since most of them are lab mouse studies. If CAL-101 is shown to have far fewer grade 3-4 infections when treating earlier stage CLL patients who are not quite this far-gone salvage cases, that would be reassuring. I touched base with Dr. Furman about my concerns. He felt it was not an issue. Nevertheless, I thought I would share it with you, just in case.
“Tis the Season to be Jolly..
I promised you a Holiday present, and this is it. Sorry it turned out to be so long, but I tried to do justice to a complicated subject. Before you start grumbling, just remember it took me a whole lot longer to research and write this article than it will take you to read it. If you don’t get all of it at one sitting, no problem, this website is not going anywhere, you can always read it again when you need to refresh your memory
With a little bit of luck, we may soon have new drugs available to us that work on a totally different basis, drugs that may prove to be effective, low toxicity and capable of giving long durations. There is a large amount of buzz surrounding these new generation kinase inhibitor drugs – which means we can hope to get credible results sooner rather than later. Keep your fingers crossed folks. We are about due for a bit of good luck and CAL-101 and the other kinase inhibitors coming down the turnpike may be what we have been waiting for.
Happy Holidays, from my family to yours. May the New Year bring you health, happiness and serenity.
CAL-101 is a hotly researched area and there are interesting developments, patient perspectives being reported. I strongly urge you to follow the discussion thread below if you want to keep up with the latest on this drug. Since our discussion sections are only open to registered members, you will have to login to read the comments of our members and my responses.