The Clinical Trial and the Patient's Voice: "I'm Extremely Lucky to Be Alive"

Wesley Hall sounds remarkably calm for someone about to start his fourth course of cancer treatment. His conversation with Evidence-Based Oncology^TM (EBO^TM) took place just after Thanksgiving, after Hall learned that his stage IV stomach cancer diagnosed in 2013 had metastasized to his liver.

At first, doctors feared the cancer had also spread to Hall’s spine and his rib, but that turned out to be a false alarm. “I was never so glad just to have liver cancer in my life,” Hall says with a laugh.

That positive outlook is hard won, for Hall has been on quite a journey. “I’m calm, because I’m extremely lucky to be alive,” Hall says. He credits oncologist Nuruddin Jooma, MD, MPH, and the team at Florida Cancer Specialists & Research Institute,¹ with “not letting any grass grow under [my] feet,” and getting him into a clinical trial within weeks of diagnosis.

By December 19, 2017, Hall had started his third clinical trial in 4 years, and the second involving immunotherapy. He is among several dozen patients taking Lycera’s investigational oral agent LYC-55716, a RORγ agonist that attacks the tumor in multiple ways. The therapy is described as a master switch, simultaneously regulating the activity of both Th17 (helper) T cells and Tc17 (cytotoxic) T cells; the manufacturer says the approach “both ‘removes the brake’ and ‘pushes on the accelerator’ of immune function.”²

For Hall, the idea of immunotherapy in a pill was a revelation. But based on experience, he still saw taking part in a clinical trial as a big responsibility—one with long days and travel at the outset for tests at Florida Cancer Specialists’ research facility in Sarasota, some 60 miles from his home in Dunedin. It’s worth it, however. Despite the adverse effects he experienced in a previous trial, and all the driving, Hall knows that he’s beaten the odds.

He is serious about his part in the scientific process. “You have to keep a log,” Hall says, because researchers want to know exactly when medications are taken. “You have to be honest.” And there’s much a person can’t consume, ranging from vitamins and herbal supplements to Florida grapefruit.

It’s not just about what the trials have done for him. Hall knows what he’s doing is part of something bigger, and the prospect of helping younger cancer patients motivates him to take part in early-phase studies. “I’ve been married 3 times so I’m not good at that,” he says. “I’m 74 years old. I figure if I can [participate in] research to help someone else, that’s fine with me. I have young friends with cancer, and my heart bleeds for them.”

Didn't know how to spell lymphoma at diagnosis

It’s been nearly 20 years since Robert Mesloh noticed what appeared to be a small cyst on his right temple one morning while shaving. He was on a business trip in Singapore, and upon returning home to New Jersey he went to his family doctor, who referred him to a dermatologist, who sent him to a surgeon to have it removed. Two weeks later came the pathology report and a late night phone call about a term Mesloh had never heard: follicular indolent non-Hodgkin lymphoma.

“I didn’t even know how to spell lymphoma, much less that it was a cancer,” Mesloh says. “But then, being a double type A personality, I had to find out as much about it as I could.”

It was the early days of the internet, but Mesloh didn’t want to rely only on that, so he connected with the group that would become the Lymphoma Research Foundation (LRF). In time, he became an LRF ambassador, testifying before Congress, traveling to annual meetings, and interacting with researchers from around the world. He’s now retired and has moved from Parsippany, New Jersey, to The Villages, Florida, but his charitable work continues.

Through the LRF, Mesloh serves as a consumer representative—a patient voice—on one board that awards research grants for cancer prevention and research within the state of Texas,³ and on another board that awards grants on behalf of the Department of Defense.

His activism, and his own deep dive into understanding lymphoma, have shown Mesloh how fortunate he was to initially find an excellent oncologist, Charles Farber, MD, PhD, who not only specialized in lymphoma but also excelled in explaining the available treatment options, limited as they were at the time.

When I had my original diagnosis in 1998, I was what they called pre-stage I,” Mesloh says, and there was a 12% chance that the surgery had removed all the cancer; Mesloh also received radiation. Five years later in 2003, he had a recurrence in the abdominal area. In that span, a “miracle” therapy had arrived: the regimen known as R-CHOP (rituximab with cyclophosphamide, doxorubicin [hydroxydaunorubicin], vincristine sulfate [Oncovin], and prednisone) had made a splash at the 2002 meeting of the American Society of Hematology.⁴ After treatment with R-CHOP, Mesloh received rituximab maintenance therapy for 2 years.

“Currently, knock on wood, I’m still in complete remission,” he says.

Mesloh was among the first group of patients to gain access to R-CHOP under general availability. Having Farber as his oncologist made all the difference, and Mesloh encourages lymphoma patients to seek a specialist. “Back in 1998, there wasn’t very much that was available,” he says, likening the era to the Dark Ages, compared with what Mesloh sees today as the Golden Age of lymphoma research.

When he was diagnosed, Mesloh says, Farber told him there were 3 to 4 types of Hodgkin lymphoma and 22 to 24 types of non-Hodgkin lymphoma. Now, “to date, we know categorically, there are 80-plus types of non-Hodgkin’s lymphoma,” he says. The completion of the human genome project and other technological advances have yielded more details about cancer subtypes, human DNA, and cancer-cell DNA, and each subtype requires a different approach.

Mesloh is keenly aware how timing worked in his favor. If his lymphoma had shown up just a few years earlier, he would have missed the broader availability of rituximab and R-CHOP “specifically for this 1 form of the 80-plus types of lymphoma.” At one point, Mesloh may not have known how to spell lymphoma, but he can now explain in detail how a monoclonal antibody attaches to the antigen on a cancer cell and “chokes it, so it can’t get any more nourishment.”

Still, those people treating Mesloh have stopped short of saying he is cured. “To this very day, I still think about it, though it’s not in the forefront of my mind,” Mesloh remarks.

Could "set the clock" by symptoms from study drug

Within weeks of his 2013 diagnosis, Hall was enrolled in a phase 2 clinical trial involving folinic acid and oxaliplatin (FOLFOX) and tivantinib, under the care of Sarasota- based researcher Manish Patel, MD.5 “That worked for 2-and- a-half years,” Hall says. (The trial results were reported this summer in Cancer Investigation.⁶) However, Hall says, “I had some pretty bad neuropathy in my hands and feet from the platinum-based drugs.”

By the end of 2015, Hall’s cancer had progressed, so he was taken off the trial and put on regular chemotherapy, staying closer to home for care. In January 2016, Patel offered Hall an opportunity for another clinical trial, this time a phase 1 study involving the immunotherapy durvalumab, the programmed cell death ligand—1 inhibitor that a year later would be granted accelerated FDA approval for certain patients with metastatic urothelial carcinoma.⁷

Hall had heard about adverse effects (AEs) from immunotherapy, but durvalumab turned out not to be the problem, although he ran a high fever of about 104 degrees for the first month or so as his immune system adjusted to the treatment. That didn’t bother him. The targeted therapy he took alongside the durvalumab was another story. The other drug, an as-yet unnamed oral WEE1 kinase inhibitor,⁸ caused intestinal AEs so toxic and predictable, Hall says, that “I could set the clock by when the symptoms were going to start [and] when they were going to stop.”

According to trial information from AstraZeneca, the WEE1 kinase inhibitor is designed to target a protein that plays a role in cell cycle progression and protein phosphorylation—a pharmacologically targetable mechanism that lets cells respond to conditions around them.⁹ Hall told EBO^TM that at the time he stopped taking the combination in November 2016—when a stomach mass reappeared after 11 months—he was the only person who had stuck with the WEE1 kinase inhibitor beyond 2 months. The trial is still recruiting patients, and notes on ClinicalTrials.gov reveal that the drug was so difficult to tolerate that the original dosing schedule was amended; it now includes 2 new schedules that add dexamethasone on the first day of the WEE1 kinase inhibitor, because patients on the first schedule experienced “dose-limiting toxicity.”¹⁰

In early 2017, Hall returned to Jooma’s practice just minutes from home, where he started on a series of radiation and chemotherapy treatments: carboplatin plus taxol. “That kind of killed everything,” Hall says.

By April 2017 he had no signs of cancer in his stomach, but once again he’d experienced neuropathy. That is why when a new tumor emerged in November 2017, Jooma and Patel wanted to try “something my body hadn’t already seen,” as Hall puts it. And so, as Christmas approached, Hall was preparing for a half-dozen trips from Dunedin to Sarasota in January, where he would put in 12-hour days having his blood drawn and getting other lab work done at the Sarasota research facility, to meet the standards needed for a clinical trial.

Each of those would be a long day for someone who doesn’t have cancer, much less someone who does, but Hall doesn’t mind. After more than 4 years, he feels a bond with both his community oncology team and his caregivers at the research center. Hall “never would have survived” at a large academic institution, he claims, and he raves, for instance, about the Thanksgiving dinner that Florida Cancer Specialists hosted for patients, complete with valet parking. “When I’m not sick, I go there and take them cookies and muffins,” he says. “They’re my family.”

In his own family, he has experienced great loss. When Hall was in elementary school, his father died; in December 2016, Hall’s middle son died of an illness caused by his work as a park ranger. Cancer has changed and shaped Hall’s reality as well, but the disease has also led to positive changes. He’s become a “gym rat,” and he enjoys advocacy work with the Community Oncology Alliance. While he doesn’t have grandchildren, he loves playing Santa for his neighbors’ children.

“I have a real calmness about the whole thing,” he says. “It is what it is. You just have to make the best of it.”

Too few patients take part in clinical trials

From his work with the LRF, Mesloh meets young researchers who are devoting their lives to finding cures for lymphoma and other cancers. “The research grants that are coming through, actually for all forms of cancer, are looking down at the molecular level of how to attack the specific forms of cancer,” Mesloh says. Studies that look to use older medications in new ways, along with genetic testing that allows for personalized medicine in cancer care, are gaining traction. By these developments, he says, “I’m very encouraged.”

Less encouraging, Mesloh says, are frustrations like the “archaic system of billing,” including the disparity between the ways infusion and oral medications are treated in some health benefit plans. (Oral therapies are sometimes treated as a pharmacy benefit with high out-of-pocket costs for patients, while infusion is treated as a medical benefit). There’s also not enough progress on sharing information among institutions, despite much talk of doing so during former Vice President Joe Biden’s Moonshot initiative.¹¹

The biggest challenge Mesloh hears about is the tiny share of patients willing to take part in clinical trials. “In the United States, only about 5% of our population who are diagnosed with a cancer will go on to a clinical trial. That disappoints me,” he says. To bring precision medicine to its potential, that percentage must grow, and it will take oncologists educating their patients and referring them outside their practices. “Too many people believe they are going to get a placebo,” Mesloh says, even though that will not happen in most cases.

In lymphoma, “we are probably a decade away from being able to manage many of these [subtypes], based on the research that is in the [pipeline] now,” Mesloh says. With the right funding, the field could see improvement on a trajectory that Mesloh calls “hockey-stick” exponential improvement, for the shape of the graph, instead of linear improvement.

For all he’s learned since his diagnosis, some of the most important conversations at Mesloh’s grant meetings come during the breaks, and they epitomize why he is there. Researchers who spend their days locked in a laboratory come talk to him, to quietly thank him for sharing what it’s like to be a patient living with the disease. “They tell me, ‘Bob, I need to be made aware of that issue. I don’t hear enough of that,’” Mesloh relates.

Epilogue

Hall was feeling good during the latest trial as he headed into his first scan on February 6, 2018. But 2 days later, he learned the news “was not what I had hoped.”

The lesion in his liver had spread, and he would have to come off the trial. Hall told EBO^TM he remains at the top of the list for any new trial that covered his situation, and he wasted no time getting in to see Jooma the day after learning the news.

Given Hall’s history with neuropathy from platinum-based chemotherapy, Jooma made plans to start a targeted therapy, to be followed by radiation.

Through it all, Hall’s optimism came through as he described “seeing my old friends,” at his appointment. He sounded hopeful about the next chapter of his journey, which would start in just 12 days.

His trust in Jooma is complete.

“I’m confident he will take good care of me.”

ACKNOWLEDGMENTS: Evidence-Based Oncology^TM would like to thank Rose Gerber of the Community Oncology Alliance Patient Advocacy Network (CPAN) for her assistance with this article. For more about CPAN, visit http://cpan.communityoncology.org/.

References:

1. Where hope is powered by science [home page]. Florida Cancer Specialists & Research Institute website. flcancer.com/en/. Accessed January 28, 2018.

2. LYC-55716 (RORγ agonist) investigational compound. Lycera website. lycera.com/scientific-approach/immune-activation/ror%CE%B3-agonists. Updated January 2018. Accessed January 27, 2018.

3. Advocate reviewers. Cancer Prevention and Research Institute of Texas website. cprit.state.tx.us/grants-process/peer-review-committees/advo- cate-reviewers/. Accessed January 27, 2018.

4. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235-242.

5. Phase I/II trial of tivantinib with FOLFOX for the treatment of advanced solid tumors and previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal junction or stomach. ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT01611857. Updated November 23, 2016. Accessed January 27, 2018.

6. Pant S, Patel M, Kurkjian C, et al. A phase II study of the c-Met inhibitor tivantinib in combination with FOLFOX for the treatment of patients with previously untreated metastatic adenocarcinoma of the distal esophagus, gastroesophageal junction or stomach. Cancer Invest. 2017;35(7):463-472. doi: 10.1080/07357907.2017.1337782.

7. Durvalumab (Imfinzi). FDA website. www.fda.gov/Drugs/InformationOn- Drugs/ApprovedDrugs/ucm555930.htm. Updated May 1, 2017. Accessed January 27, 2018.

8. Safety, tolerability and pharmacokinetics of AZD1775 plus MEDI4736 in patients with advanced solid tumors. Smart Patients website. smartpatients. com/trials/NCT02617277. Updated January 2018. Accessed January 27, 2018.

9. Reimand J, Wagih O, Bader GD. The mutational landscape of phosphoryla- tion signaling in cancer. Sci Rep. 2013;3:2651. doi: 10.1038/srep02651.

10. Safety, tolerability and pharmacokinetics of AZD1175 plus MEDI4736 in patients with advanced solid tumors. ClinicalTrials.gov website. clinicaltrials. gov/ct2/show/NCT02617277. Updated January 9, 2018. Accessed January 27, 2018.

11. Cancer Moonshot. National Cancer Institute website. cancer.gov/research/ key-initiatives/moonshot-cancer-initiative. Accessed January 28, 2018.

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