Avastin Combo trials Halted!! Combo drug is Sutent!

[RandyW]

Avastin Combo Trials Stopped Over Adverse Outcomes

Date Published: Tuesday, July 15th, 2008

Genentech Inc., has just sent out a written warning to doctors about a type of anemia seen in patients treated with its popular cancer drug Avastin—bevacizumab—when taken with Pfizer Inc.’s Sutent in a clinical trial. The cases of microangiopathic hemolytic anemia (MAHA) seen in a Phase 1 kidney cancer study prompted the closure of a mid-stage trial of Avastin plus Sutent, Genentech said in a letter to doctors posted on the Food and Drug Administration’s (FDA) website.

The Avastin-Sutent combination is neither approved nor recommended according to the Genentech letter. Avastin, stops blood supply to tumors and is approved to treat colon, lung, and breast cancer. Sutent—generically known as sunitinib malate—is one of the most widely used medicines for the treatment of advanced kidney cancer. Avastin, considered Genentech’s most important product, is being tested in combination with other drugs in a variety of clinical trials.

The letter noted that five of 12 patients who received the highest Sutent dose had laboratory findings consistent with microangiopathic hemolytic anemia. In the study, 25 patients were studied and groups were given Sutent in escalating doses in a four week on and two week off schedule. Two cases were considered severe with evidence of several adverse side effects, including—but not limited to—severe high blood pressure. Genentech spokeswoman Kimberly O’Campo said other studies combining lower doses of Sutent with Avastin are ongoing.

Meanwhile, two other mid-stage studies of Avastin in combination with Sutent and chemotherapy were stopped over poor tolerability involving fatigue, gastrointestinal complications—diarrhea, anorexia, dehydration, and stomatitis—and myelosuppression, which is a condition in which blood cell and platelet production is reduced. O’Campo noted that those trials involved patients with breast and lung cancer.

Analysts are looking for second-quarter U.S. Avastin sales of over $640 million when Genentech announces its quarterly results this week. Genentech shares were down $2.36, or 3 percent, to $75.39 on the New York Stock Exchange.

Avastin is prescribed as a last beacon of hope in often hopeless situations. But, Avastin does not come cheap, can run around $100,000 annually, is not without controversy. Studies show Avastin only prolongs life by a few months, if that. Newer studies suggest the drug might be less effective against cancer than the FDA understood when it first approved Avastin. While many patients and their doctors say the drug can improve the quality of life by providing intangibles such as a sense of well-being and an ability to carry out daily tasks without exhaustion or pain, these benefits are difficult to monitor and document. And, now, many patients with other cancers are taking Avastin, despite that there is no compelling evidence that helps. Avastin also has serious, sometimes lethal side effects.

Avastin is generally used in conjunction with standard chemotherapy and does not work as well when used alone, meaning that patients are still subject to chemotherapy’s side effects. Also, Avastin’s cost to patients and insurers can be higher because doctors and hospitals buy Avastin and then sell it to patients or their insurers, often marking up the price.

This entry was posted on Tuesday, July 15th, 2008 at 11:08 am and is filed under Legal News, Pharmaceuticals.

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[gpawelski]

True synergy is rather uncommon in most adult solid tumors. Most drug combinations in diseases such as cancer are merely additive, where the whole equals the sum of its parts, and not synergistic.

In cases where drugs are only additive and not synergistic, nothing is learned by testing the drugs in combination over what is learned by testing them separately. So drugs in combination are only tested in cases where there is the realistic possiblity of seeing true synergy.

The best combinations are those in which there is true synergy and in which the toxicities of the drugs in the combination are non-overlapping, so that full doses of each drug may be given safely.

The theory behind combination chemotherapy is that you can't give full doses of all drugs when you give them together. They have overlapping toxicity, which means you need to cut the doses when you give them together, so you get down to "homeopathic" dose levels.

Pharmaceutical companies have been attracted to studies looking at the maximum tolerated dose of any treatments. Cancer sufferers have been taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need.

Many of the highly expensive targeted cancer drugs may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses. The search for minimum effective doses of treatments should be one of the key goals of cancer research.

Molecular testing methods detect the presence or absence of selected gene mutations which theoretically correlate with single agent drug activity (either Avastin or Sutent). Tests are performed using material from dead, fixed or frozen cancer cells, and are never exposed to anti-cancer agents.

Cell culture methods assess the net effect of all inter-cellular and intra-cellular processes occurring in real-time when cells are exposed to anti-cancer agents. Tests are performed using intact, living cancer cells plated in microclusters. It allows for testing of different drugs within the same class and drug combinations to detect drug synergy and drug antagonism.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007

Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp. 31e-32

[RandyW]

Thanks Greg!!Never thought of that

[gpawelski]

There are some researchers like UC Berkeley's professor of molecular and cell biology, Peter Duesberg that argue against "mutation" theory of cancer. After thirty-six years into the war on cancer, scientists have not only failed to come up with a cure, but most of the newer drugs suffer from the same problems as those available in the pre-war days: serious toxicity, limited effectiveness and eventual resistance.

According to the countervailing "chromosomal" theory of cancer, each cancer is unique, and there is no magic bullet. The mutation theory of cancer says that a limited number of genes causes cancer, so cancers should all be more or less the same. The chromosomal theory implies instead that even if cancers are from the same tissue, and are generated with the same carcinogen, they are never the same. There is always a cytogenetic and biochemical individuality in every cancer (this is why I am such an enthusiast for functional profiling assays).

For decades, scientists have been trying to get around the drug resistance that is characteristic of all cancers. Some say, not a single drug or combination of drugs has succeeded.

The assumption behind all the efforts has been the gene mutation theory of cancer. Mutated genes somehow either cause cancer directly or inactivate genes thought to guard against cancer, the so-called oncogenes and tumor suppressor genes. However, there is no functional proof that the gene mutation theory is correct.

The gene mutation theory of cancer hasn’t yet produced the types of breakthroughs we all want. Everyone in cancer research seems to have centered their attention on gene being the culprit. It would be expected that after more than a century of pursuing this one angle, and the numerous links that have been made, this should have lead to more progress than is presently observed.

Sequencing the genome of cancer cells is explicitly based upon the assumption that the pathways of tumor cells can be known in sufficient detail to control cancer, an assumption that some scientists believe to be false. The assumption that the pathways of tumor cells can be known in a patient with metastatic cancer is logically inconsistent with the reality of tumor cell evolution.

The problem is that a patient with metastatic cancer can have billions of unknown cancer cells disseminated throughout the body at unknown locations. Each cancer cell can be different. And the cancer cells that are present change and evolve with time.

There is another effort in research called the chromosomal theory of cancer. Even if cancers are from the same tissue, and are generated with the same carcinogen, they are never the same. There is always a cytogenetic and a biochemical individuality in every cancer.

Further information on the work of Peter Duesberg:

http://www.medicalnewstoday.com/articles/75540.php

[Barb73]

Thanks, George, for the in-depth explanation of the chromosomal theory involving cancer.

I went on to read the article and was fascinated.

It is very difficult for scientists (I would imagine) to abandon what has been an ongoing theory (mutation theory) for so many decades.

As they say, (paraphrasing) "Insanity is doing the same thing over and over and expecting different results."

My mother was cured of colon cancer (no radiation/no chemo) even though after an extensive colon resection, the doctor had left the satellite tumors in her liver.

He told us he had no idea of what the prognosis would be.

This may explain Duesberg's theory of the individuality of cancer.

My mother died 22 years later, from COPD. She outlived the doctor who had been was her hero. Her grief at his death was inconsolable.

Barbara

[gpawelski]

Wow! Outlived the surgeon!

I still keep in touch with my wife's thoracic surgical oncologist. Just like a trauma victim will love forever the surgeon who fixed his/her compound fracture, the cancer patient (and their loved-ones) feels genuine, heartfelt gratitude to the oncologist during periods when the cancer crab retreats. And it retreated with her surgery.

I think, like your mother's doctor, even though after an extensive extrapleural lobectomy (a.k.a. the "shark bite" scar), which the transdiaphragmatic tumor was up against her liver, the surgeon thought she may have left satellite tumors somewhere in her body, but she had no idea of what the prognosis would be.

This surgeon stated that she was 100% successful and did not feel that further treatment was indicated. A number of thoracic surgeons over the years told me that she was just trying to make my wife disease free. Recurrent cancer patients can live a long time with a thorough surgical intervention.

There are microscopic cancers that will never cause us problems. We all have abnormal cells, but most of us will not die from cancer. Pseudodisease is most common in prostate and breast cancer, and is an issue for kidney, lung and melanoma cancers.

Greg

[Barb73]

Dear Greg,

Sorry I mixed you with some "George" in my ether world.

Thank you for the reply. Sometimes, I live in the past. My mother was our prime example to tell to others to give hope.

Why she lived so long was a wonderment to us all. As it turns out, she may have just beat the thing with the surgery being the major interaction.

My sister is a breast cancer survivor, and also a uterine cancer survivor. Those both occurred in her thirties and early forties. She is now 70.

Our grandmother survived breast cancer in her sixties, AND lived to be 89 years old. God bless her indomitable spirit. She was a fantastic woman.

Cancer, thankfully, did not kill our women in our family. However, in Bill's family there have been cancers that did.

Bill and his brother are the only two still alive and kicking. His brother survived an extremely aggressive prostate cancer.

Well, Greg, I hope that if you are right and the theory the researchers are pursuing is wrong, at very least, we can all hope for the drugs they have will delay the inevitable for longer and longer periods. Perhaps, they will live a long life due to various interventions, and who will care if they didn't achieve a cure?

I hold onto hope, and Bill (who is presently enjoying a lot of good time) will benefit for as long as he can hold steady.

You and I have been the caregivers. We know how painful it is to watch our loved ones face this horrid disease, cancer. But, Greg, we do the best we can with what we have to offer them.

I may never have someone to care for me in my last days. Bill knows this, and maybe he thinks he may not be so bad off.

Barbara