Patients need to be patient (pun intended!)

half glass of wineLate last year I published a positively rosy article titled “CAL-101: Dawn of a new era“.  Fortunately the subtitle “At last, aGleevec” of our own?” had a question mark at the end of it, giving me a little bit of cover.  ASCO 2011 has an important abstract on how CAL-101 performed in an early Phase-I trial with previously treated CLL patients.  I thought you would want to see it.  The abstract is below, followed by my two cents. And an editorial on the importance of patients being patient in their assessment of new drugs.

2011 ASCO Annual Meeting

J Clin Oncol 29: 2011 (suppl; abstract no.  6631)

Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3‑kinase P110d, in patients with previously treated chronic lymphocytic leukemia.

Author(s): S. E. Coutre, J. C. Byrd, R. R. Furman, J. R. Brown, D. M. Benson, N. D. Wagner-Johnston, I. W. Flinn, B. S. Kahl, S. E. F. Spurgeon, B. J. Lannutti, H. K. W. Hsu, R. Ulrich, S. Peterman, L. Holes, L. L. Miller, A. S. Yu; Stanford Cancer Center, Stanford, CA; The Ohio State University Comprehensive Cancer Center and Arthur G. James Cancer Hospital and Solove Research Institute, Columbus, OH; Weill Cornell Medical College, New York, NY; Dana-Farber Cancer Institute, Boston, MA; The Ohio State University, Columbus, OH; Washington University School of Medicine, St. Louis, MO; Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN; University of Wisconsin, Madison, WI; Oregon Health & Science University, Portland, OR; Calistoga Pharmaceuticals, Seattle, WA

Disclosures

Background: 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. CAL-101 is an isoform-selective inhibitor of PI3Kδ that induces apoptosis of chronic lymphocytic leukemia (CLL) cells. Methods: This phase I study evaluated CAL-101 in patients with previously treated hematologic cancers. CAL-101 was administered orally 1 or 2 times per day (QD or BID) continuously in 28-day cycles, until disease progression or unacceptable toxicity. Efficacy analyses were based on standard criteria. Results: At data cutoff, the study had enrolled 54 patients with CLL. Patient characteristics included: median [range] age of 62 [37‑82] years; 82% males; 72% with refractory disease, 81% with bulky disease, 36% with del(17p), and a median [range] of prior therapies of 5 [2‑15]. CAL-101 dose levels were 50 mg, 100 mg, 150 mg, 200 mg, and 350 mg BID; and 300 mg QD. The median [range] of CAL‑101 treatment cycles was 8 [1-19]. Grade ≥3 adverse events included pneumonia (24%), neutropenia (24%), thrombocytopenia (7%), neutropenic fever (7%), anemia (6%) and ALT/AST increase (6%). CAL‑101 reduced lymphadenopathy by ≥50% in 80% of patients. A transient increase of >50% from baseline in peripheral absolute lymphocyte counts occurred in 58% of patients. The overall intention-to-treat response rate by IWCLL 2008 criteria was 26%. Medians for duration of response and progression-free survival had not been reached (>11 months), with 46% of patients continuing on treatment. CAL-101 reduced constitutive overexpression of phospho‑AKT in patient CLL cells and normalized plasma concentrations of CCL3, CCL4, and CXCL13. PK analyses showed minimal increases in plasma Cmax and AUC at doses >150 mg BID. Accrual is ongoing and updated data will be presented. Conclusions: CAL-101, an oral PI3Kδ-selective inhibitor, shows acceptable safety and promising clinical activity in heavily pretreated patients with CLL. Dose‑response assessments support the 150 mg BID dose for future single-agent and combination chemo/immunotherapy studies.

The author list is very impressive, as is also the list of high pedigree research institutions that participated in this study.  While you are about it, you should also click on the link to the financial disclosures , it makes for interesting background.  Along the same lines, I hereby disclose I received no money or any other favors from Calistoga Pharmaceuticals and neither I nor my family own a single stock in the company :)

Since this abstract is the only document to go by, we have access to only this limited amount of information.  Down the road, I hope we will have more detailed journal articles describing this study and its results.

  • 54 previously treated CLL patients were enrolled in this Phase-I study. Patients took CAL-101 (orally taken pill) 1 or 2 times a day for 28 day cycles.  Treatment continued until the patient’s disease progressed or there was unacceptable toxicity.
  • No question, this was a tough crowd of patients. Median age was 62 (OK, that is not too far gone). But 72% had refractory disease (remember, “refractory” is far worse than merely “relapsed”). 81% had bulky lymph nodes, which makes it harder for many drugs to work (Campath is ruled out in such cases, for example). 36% of the patients had the high risk 17p deletion (FISH test).  On average, patients had been around the block more than a couple of times.  As a matter of fact, they had been in therapy 5 times before.
  • Since this was a Phase-I trial, one of the most important objectives was finding the right dose for the drug.  In the patients that took the pill only one time per day, the dosage was 300mg.  Patients who took the pill twice daily ranged over the dosage of 50mg – 350mg.
  • Once again, we are given the adverse effects only in terms of “greater than or equal to grade 3″.  In other words, pretty heavy duty stuff.  You need to know these grade levels.  Grade 1 is sissy stuff.  Grade 2 will get you a little sympathy from your friends and family.  Grade 3 and 4 will require medical advice / intervention most likely. Grade 5 means you won’t be needing your doctors any more since you would no longer be living.
  • Just about a quarter of the folks had pneumonia, same number had neutropenia.  So, if you thought CAL-101 is without infection risk, you (and me) were a little off the mark.
  • Continuing the list, risk of decreased platelets was ‘only’ 7%; neutropenic fever and anemia were also in the same ballpark.  I was pleased to see liver toxicity (measured by ALT/AST) was only 6%.  I would have expected higher level of liver toxicity.
  • Now for the results: Bulky nodes were reduced by 50% or more in 80% of the patients. This is actually pretty impressive stuff, especially since these were pretty heavily pre-treated patients and bulky nodes are a lot harder to treat than simply reducing white blood counts. (I wonder how they measured amount of reduction – was it merely by feel or did they do CT scans?  Hand measurement is notoriously prone to observer / researcher bias).
  • There was the expected rise in WBC increase in about half the patients.  Expected, since it is now well understood all of those CLL cells getting flushed out of the lymph nodes have to go some where, and the likely place is out into open blood circulation.
  • The overall response rate was 26%. Remember, this include complete and partial responses.  I must confess I was hoping this would be higher.
  • This abstract made no mention about bone marrow status.  That really bugs me. There is some information floating out there that CAL-101 does not do a good job of clearing CLL infiltrated bone marrow. Reassurances to the contrary, I continue to think this is an important issue.  A heavily infiltrated bone marrow cannot do its job of producing all the different blood cell lines.  Infiltrative Rai stage – IV is pretty heavy duty stuff.
  • The study has not been going on long enough to get a good fix on remission length.  But 46% of the patients are still taking the drug (remember, they were taken off the drug only if their disease progressed or there was too many adverse effects).  So, if I am reading the tea leaves right, 54 % of the patients went off the study because they progressed, had too many adverse effects – within an average of 11 months since start of the study?
  • They sorted out the drug dosage bit.  In future we are going to be seeing 150mg twice daily as the standard dosing.

Editorial

It is hard to be patient when you are facing life or death issues.  It is all too easy to wish for rapid turnround in drug approval process, cut a few corners in scientific or ethical considerations, if it means we will have access to the latest sexy drug candidate.  Wishful thinking gets to all of us. Me included, my last article on the subject of CAL-101 had the very rosy title of “Dawn of a new era”.   But clinical trial process takes a long time.  Especially when we are dealing with long fuse cancers such as CLL.  How can we tell whether or not a new drug is safe, whether it will actually do any good, prolong remissions and overall life, unless we do the hard work of clinical testing in well conducted clinical trials?  How can we judge the validity of results until they have been subjected to the scrutiny of peer review? Statistically valid results do not guarantee that an individual patient will get exactly the same result – but they sure as hell give him a fighting chance of not buying a pig in the poke!

It is all too easy to look for scapegoats (the FDA is a popular target). Be very careful what you wish for folks.  Next time you are tempted to lynch the FDA drug approval committees, be sure you understand they stand between you and careless research – if not downright self-serving and / or  fraudulent results.  Before you get suckered into rabble rousing on internet chat rooms, be sure you take a second look at the potential conflicts of interest.  Everyone has agendas.  I will be the first one to point out, patient advocates are no exception either – all of which means you need to be your own best advocate!

My initial response to this early phase clinical trial results was dismay.  I hoped for much better results.  A second and third careful reading took away some of the initial angst.  This glass is definitely not full, but in my layperson opinion it is not completely empty either.  As the title of this article indicates, I call this a half-full glass. And it is important not to throw the baby out with the bathwater.

These were extremely advanced cases, most of the patients had very poor prognosis going into the trial.  CAL-101 did not perform a miracle, but it did get a fair amount of responses.  Will it work better in a less tough crowd, patients with less advanced disease?  Obviously.  Most drugs work better when they are not fighting an uphill battle.  Will CAL-101 do better if coupled with other drugs that work well in tandem with it?  I hope so – and I think there is good reason to hope for that.  When results are published from more late stage trials, I will be sure to review them for you.  You can then judge for yourself whether the glass is half full or half empty.

Postscript

Dr. Susan O’Brien of M. D. Anderson is a well known CLL expert.  She gave a recent interview on the subject of kinase inhibitors such as CAL-101 and PCI-32765.  You can read her comment by clicking on this link.

clinical trials