Clinical Trials: they are not designed only to be a “last resort”

Yep, my trial was a single-site trial at MD Anderson in Houston. Amazing place with so much cutting-edge work going on.

The trial was independent of traditional mutations, just requiring tumor tissue to express the TROP2 protein. They have a custom line of stem cells derived from preserved/donated umbilical cord blood. The Natural Killer (NK) cells are engineered to recognize and attack cells that express TROP2 while leaving healthy cells alone.

They used a similar approach with good success a few years ago to target other cancer types, and I think the delivery method was intravenous. My trial was open for 3 diseases (two gyno types: ovarian cancer and mesonephric-like adenocarcinoma) and pancreatic, as long as there was metastasis to the peritoneum (common in all 3 cancer types). These cells were injected into the peritoneal space rather than intravenously, with the idea they would make direct physical contact there, but also be absorbed into the bloodstream and be distributed systemically.

It was a Phase-1, first-in-human (FIH) trial, and I was patient #5 overall, #2 for pancreatic, and at the 2nd of 3 planned dose levels to be tested. There was really good in-vitro data for it, and good results from similar intravenous treatment with other cancer types, but very little else to go on other than faith. I didn't really have a good opportunity to wait for the next dose level or success signals from previous patients.

I don't have any news about how it's going for other participants, but the 4-month chemo holiday without a successful response in the trial may be my eventual undoing. That stomach blockage I mentioned is now way too tight to pass a stent (much less liquids or food) through, so we're adding some radiation to try and reduce it enough for a stent. Low odds, but we might see results in a few weeks. Meanwhile, I'm not allowed to eat or drink anything but ice chips. I've got a new gastric drain/vent tube inserted to relieve stomach pressure, and a new chest port to get central nutrition (TPN) delivered into a vein. I miss coffee!!!

Another downside to this is that I've lost about 20 pounds, a lot of muscle mass, and since I can't even take an oral pill, there are a lot of trials I won't qualify for. 🙁

Yep, my trial was a single-site trial at MD Anderson in Houston. Amazing place with so much cutting-edge work going on.

The trial was independent of traditional mutations, just requiring tumor tissue to express the TROP2 protein. They have a custom line of stem cells derived from preserved/donated umbilical cord blood. The Natural Killer (NK) cells are engineered to recognize and attack cells that express TROP2 while leaving healthy cells alone.

They used a similar approach with good success a few years ago to target other cancer types, and I think the delivery method was intravenous. My trial was open for 3 diseases (two gyno types: ovarian cancer and mesonephric-like adenocarcinoma) and pancreatic, as long as there was metastasis to the peritoneum (common in all 3 cancer types). These cells were injected into the peritoneal space rather than intravenously, with the idea they would make direct physical contact there, but also be absorbed into the bloodstream and be distributed systemically.

It was a Phase-1, first-in-human (FIH) trial, and I was patient #5 overall, #2 for pancreatic, and at the 2nd of 3 planned dose levels to be tested. There was really good in-vitro data for it, and good results from similar intravenous treatment with other cancer types, but very little else to go on other than faith. I didn't really have a good opportunity to wait for the next dose level or success signals from previous patients.

I don't have any news about how it's going for other participants, but the 4-month chemo holiday without a successful response in the trial may be my eventual undoing. That stomach blockage I mentioned is now way too tight to pass a stent (much less liquids or food) through, so we're adding some radiation to try and reduce it enough for a stent. Low odds, but we might see results in a few weeks. Meanwhile, I'm not allowed to eat or drink anything but ice chips. I've got a new gastric drain/vent tube inserted to relieve stomach pressure, and a new chest port to get central nutrition (TPN) delivered into a vein. I miss coffee!!!

Another downside to this is that I've lost about 20 pounds, a lot of muscle mass, and since I can't even take an oral pill, there are a lot of trials I won't qualify for. 🙁

I was just started on Lumakras because I wasn’t recovering from chemo. It’s an inhibitor that was intended for lung cancer but they found it works for pc with kras g12 gene. I hope it works!

Marcia, do you have G12V? Also, do you have Lynch?

I just wanted to add a caveat that, although clinical trials are not "only intended to be a last resort," they should not be taken lightly.

In some trials, you may receive the standard of care or the standard of care plus a trial drug/therapy. For other trials you have to be completely off all other drugs/therapies to test only the trial drug by itself.

I've been Stage-IV PDAC for almost 2 years now, but with pretty good control over everything. After 15 months on SoC therapy (Gem+Abrax+Cis), we started seeing signs and hints (but not definitive evidence) of drug resistance. My neuropathy was getting worse, my bone marrow and bloodwork were taking a beating, I had a break in my work schedule, and an opportunity to participate in a very promising, cutting-edge trial.

Two independent oncologists agreed it was good timing and the right thing to do, so I jumped through all the hoops and was accepted into the trial.

The trial required at least 4 weeks washout from any previous chemo, followed by 7 weeks in the treatment / observation phase. Insurance issues, travel, and other logistics added about 2 weeks, making a 13-week (3-month) period off chemo before I got final results.

Unfortunately, the treatment did no good at all. Cancer grew and spread during that time period instead. We were able to revert to and resume my previous chemo within two weeks of those final results, but the tumor growth didn't just stop on a dime. The primary tumor continued to advance, and within two weeks, landed me in the hospital with an intestinal blockage where I am today, awaiting placement of a stent to open the blockage so I can eat again.

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In hindsight, a few months before the hints of drug resistance developed, one of my oncologists said I was responding so surprisingly well to the GAC for so long that it would border on unethical to go off it for a trial of unknown efficacy. Although I did reach the point where the trial made sense, the "unknown efficacy" part (which turned out to be zero) was a real disappointment.

Phase-1 trials offer a lot of innovative and promising treatments, but their primary purpose (along with testing effectiveness) is to identify dose-limiting toxicities and recommended dosing for Phase-2 trials. Phase-2 seems to be a sweet spot somewhere between Phase-1 (being a guinea pig) and Phase-3 (risk of placebo).

I thought this was important enough to share. I hope my lesson from this is a benefit to someone!

Thanks for information about Phase 2 trials being a sweet spot. I do wonder about the use of placebos in Phase 3 if a Phase 2 trial has shown good results. Other than following the historically defined requirements for clinical trials, if the likely result of not receiving a treatment is death, wouldn't the Phase 2 trials be just as informative? With patient medical data recorded in electronic medical databases, isn't there already an abundance of data on disease progression associated with diagnoses and genetic testing that provides virtually the same information as placebo? Besides, in a Phase 3 test with a smaller number of participants, wouldn't the calculated efficacy be more dependent on "the luck of the draw", that is the individual biologies & stamina of the participants rather than the drug being tested?

No cancer trial uses a placebo including phase III. That is considered unethical to deprive a patient of a treatment. All phase III trials unless it is a new class of drug uses the current standard of care as the control arm for comparison to the test arm.

Phase II trials are limited in the number of patients enrolled. That cohort has higher eligibility requirements of being much healthier. The eligibility requirements for phase III are more reflective of the real world. The cohort consists of over a thousand patients whereas a phase II trial may range from 25-125 patients. Patients ina phase III trial can have an ECOG physical assessment score of II or III whereas in Phase I, the score needs to be better at 0 or 1.

With a much higher number of participants, the statistical data between control and test group becomes more accurate. A good example of a recent trial that looked very promising was CPI-613 (Devimistat) from Raphael Pharmaceutical. The limited data from the phase II trial was extremely encouraging. But one needs to keep in mind the test cohort included only the healthiest patients with an ECOG PS score of 0 or 1. The investigational new drug generated a lot of excitement and quickly moved to phase III with a very large cohort now including those with ECOG PS of 2-3. Raphael Pharmaceutical began planning for FDA approval and hiring personnel and arranging for increased production of Devimistat. When the team of biostatisticians did the statistical analysis between control and test groups, the trial fell apart. There was no significant statistical difference between the control and test participants.

How could this be? It goes back to using a small, limited cohort size of participants that were relatively healthy (ECOG 0 or 1). The phase III trial was more representative of real-work, conditions-it included patients whose cancer had spread further and the impact to their physical health was much more significant resulting in the higher ECOG PS of 2 and 3.

Another recent clinical trial,drug this happened to was SM-88 (Racemetyrosine) by Tyme Pharmaceutical. The same thing happened where the drug looked great in a small, healthier cohort with limited data. Once the trial was expanded to be more reflective of real-world conditions, it failed the end-point objectives stated by the study team/trial sponsor as not showing equal or better performance than an existing treatment- (overall response rate and progression free survival are frequent metrics used to gauge treatment effectiveness).

No cancer trial uses a placebo including phase III. That is considered unethical to deprive a patient of a treatment. All phase III trials unless it is a new class of drug uses the current standard of care as the control arm for comparison to the test arm.

Phase II trials are limited in the number of patients enrolled. That cohort has higher eligibility requirements of being much healthier. The eligibility requirements for phase III are more reflective of the real world. The cohort consists of over a thousand patients whereas a phase II trial may range from 25-125 patients. Patients ina phase III trial can have an ECOG physical assessment score of II or III whereas in Phase I, the score needs to be better at 0 or 1.

With a much higher number of participants, the statistical data between control and test group becomes more accurate. A good example of a recent trial that looked very promising was CPI-613 (Devimistat) from Raphael Pharmaceutical. The limited data from the phase II trial was extremely encouraging. But one needs to keep in mind the test cohort included only the healthiest patients with an ECOG PS score of 0 or 1. The investigational new drug generated a lot of excitement and quickly moved to phase III with a very large cohort now including those with ECOG PS of 2-3. Raphael Pharmaceutical began planning for FDA approval and hiring personnel and arranging for increased production of Devimistat. When the team of biostatisticians did the statistical analysis between control and test groups, the trial fell apart. There was no significant statistical difference between the control and test participants.

How could this be? It goes back to using a small, limited cohort size of participants that were relatively healthy (ECOG 0 or 1). The phase III trial was more representative of real-work, conditions-it included patients whose cancer had spread further and the impact to their physical health was much more significant resulting in the higher ECOG PS of 2 and 3.

Another recent clinical trial,drug this happened to was SM-88 (Racemetyrosine) by Tyme Pharmaceutical. The same thing happened where the drug looked great in a small, healthier cohort with limited data. Once the trial was expanded to be more reflective of real-world conditions, it failed the end-point objectives stated by the study team/trial sponsor as not showing equal or better performance than an existing treatment- (overall response rate and progression free survival are frequent metrics used to gauge treatment effectiveness).