Chapter 9: Designing a Phase II Trial for MEPACT, and the Characteristics of Translational Research
Files
Description
In this Chapter, Dr. Kleinerman tells the next part of the MEPACT story: designing a Phase II trial. She sketches the practical elements of submitting a proposal and notes ways in which it was innovative.
Dr. Kleinerman explains how she designed the Phase II trial and the unusual parameters she set for selection patients. “I was one of the cowboys at MD Anderson.” Dr. Kleinerman explains that MD Anderson had a culture of using pioneering approaches to treat cancer.
Dr. Kleinerman describes the protocol and some surprising initial results that came from the Phase II trial and demonstrated the effectiveness of MEPACT on pulmonary metastases.
Identifier
KleinermanES_02_20140529_C09
Publication Date
5-29-2014
City
Houston, Texas
Interview Session
Eugenie Kleinerman, MD, Oral History Interview, May 29, 2014
Topics Covered
The Interview Subject's Story - The ResearcherThe Researcher Discovery, Creativity and Innovation Professional Practice The Professional at Work Discovery and Success Institutional Mission and Values MD Anderson Culture Multi-disciplinary Approaches Understanding Cancer, the History of Science, Cancer Research MD Anderson History MD Anderson Impact Controversies
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
Disciplines
History of Science, Technology, and Medicine | Oncology | Oral History
Transcript
Tacey Ann Rosolowski, PhD:
Right, right, right. I had a question and lost it. Sorry. It will come back to me. (laughs) So, next steps?
Eugenie Kleinerman, MD:
So we finished the Phase 1, we had the dose, and now we’re ready to go into Phase 2, and, of course, I wanted to do it in relapsed osteosarcoma. Well, at this point I had never written a clinical trial, knew nothing about clinical trials and what you had to do. There was nobody in pediatrics who had really written a clinical trial that could guide me. Norman Jaffe did clinical trials with high-dose methotrexate years ago, but things had changed so much. So I went to my colleagues in Cancer Medicine. Mary Silverstein was in leukemia, and she sat down with me and says, “Okay, here’s a template, and here’s what you have to do.” I talked to people in the IRB. “Here are the things you have to do.” And I just sort of took—here are examples of Phase 2 trials, and I took Phase 2 trials and read it. I knew the design that I wanted and then read it to figure out how I needed to write, you know, what the specific gains were, how to lay it out. The layout of it’s very specific. You have to have a specific layout. The things that you have to cover in terms of the sponsor and follow-up and informed consent, and all of those things I had absolutely no clue about. Now, in designing the clinical trial, again, the usual design of a Phase 2 trial is that you treat relapsed patients who have not responded to the standard of care or any follow-up salvage care, and you treat them in the setting of disease. Well, I knew from Dr. Fidler’s work that there was no way that we would ever see a positive response if patients had bulk tumor, because he had shown definitively in the mouse that this immune-therapy could only get rid of minimal residual disease, microscopic disease. So I knew I had to be very careful, because if I did it in the setting of bulk disease and it didn’t work, that would be the end of the therapy. Nobody would be interested. That would be gone. So how was I going to design a trial where the therapy could work? Well, fortunately, osteosarcoma lends itself very well, because when patients relapse, they usually relapse in the lung, and the approach is to resect the lung metastases, so you are putting the patient in the setting of minimal residual disease. But we know there are cells left behind because if you don’t do anything, 85 percent of patients will come down with more pulmonary metastases within a year. So from the time of surgery to one year, 85 percent of patients will relapse. I had researched this. I had gone to the literature and looked at what people had published, thinking about how I was going to design this. What is known about relapsed osteosarcoma? And what I also learned is there have been groups that resected the lesion and gave patients follow-up chemotherapy with agents that they hadn’t seen before, and there were some people who didn’t do anything, and it made no difference, that these salvage chemotherapies really were not effective in changing patient outcome. You may get disease shrinkage, but in terms of outcome, it made no impact. Now, back then people said, “No, that’s not true,” but I think now today people are finally—have done the experiment over and over and over and over again and see that we’re not making any impact when you just use chemotherapy. So I was ahead of my time, probably too early and caused me a lot of grief, but that’s the way it goes, right? For pioneers, that’s the way it goes. (laughs) So the way I designed the trial was patients would have to have had surgical excision of their lung metastases within one month of starting therapy with MTP. It was an arbitrary selection, because I figured to get patients here, I’m going to have to do a national. I’m going to have to open it up. I can’t just do it here, because there are not going to be enough patients. I needed about thirty patients for the trial. And what I proposed is I want to examine what is the impact on the disease-free survival, using the established data showing that if you resect lesions by one year, 85 percent have relapsed. So I said, okay, if we resect lesions and we treat with MTP, let’s see if we can increase the number of patients who are disease-free in a year. This was a new concept. Only at MD Anderson would this have been allowed to proceed.
Tacey Ann Rosolowski, PhD:
Why? Kind of tell me how that is true.
Eugenie Kleinerman, MD:
Because you just didn’t do a Phase 2 trial in the setting of minimal residual disease. You did it show if a therapy was effective. You had to show that it could shrink the tumor. Immune-therapies were just emerging and nobody really—I understood the concept because of the basic science that Dr. Fidler did. Most clinicians come to it showing, here’s it in the lab, and you give it to animals and it shrinks the tumor. Okay, now let’s take it to the clinic.
Tacey Ann Rosolowski, PhD:
You know, I had a question that’s kind of been simmering in my mind for about a half an hour, which is about translational research. And you had mentioned the term much earlier in the interview, talking about how Dr. Fidler was always—had that in mind but needed a clinical partner, and obviously you were thinking about it. And this was really at a formative time. I mean, people were just beginning to do this, so you’re not only pioneering immunology and treating pediatric patients, but you’re also working with him and pioneering what does a translational study look like and how does it shape the kinds of questions we ask and how we design our work. So that’s kind of amazing. I mean, that must have been really, really exciting to be involved in all of that.
Eugenie Kleinerman, MD:
Yes, it was exciting, but I took a lot of beatings for it.
Tacey Ann Rosolowski, PhD:
Did you?
Eugenie Kleinerman, MD:
I did. I did.
Tacey Ann Rosolowski, PhD:
Tell me about that.
Eugenie Kleinerman, MD:
I think most of the accepted pediatric oncology community thought I was one of the cowboys at MD Anderson, you know, and what did I know, and really were unwilling to listen, because “That’s not the way we do things.” But I knew that it was right. I just knew it. And fortunately, I had Dr. Fidler as a mentor and a supporter, and I had Dr. Krakoff, who was chief of Cancer Medicine at the time, who was very open to new ideas and listened and said, “Oh, gee, that makes sense,” rather than, “No, you can’t do it that way because that’s not the way you do it. That’s not the acceptable way.”
Tacey Ann Rosolowski, PhD:
And you said just a few moments ago that only at MD Anderson could you have done this. Why was that the case?
Eugenie Kleinerman, MD:
Because that’s the tradition. That was the tradition at MD Anderson. We do things that nobody else will do. We pioneer how to treat cancer, and we just are not locked into the acceptable way of doing things. And if you have a good idea and it’s reasonable and it’s safe and the IRB can find that there’s no risk to patients in terms of the things that—and you do it properly with informed consent and you let the patients know and the families know, why not? Why not try? What do we have for these patients? What are we saving these patients—what are we saving these children from? Here you have a drug that doesn’t cause hair loss, that doesn’t cause vomiting, you have some fever and chills that you’ve shown you can control in the Phase 1 trial, you have a disease that relapses in the lung where we can take out the tumor but we’ve got no therapy afterwards. You know, why are we saying no because nobody else has done it this way? That’s what MD Anderson does. We are the pioneers. We do it first. We show the world. So that was the mentality. So I designed the trial and I had support of my adult sarcoma physicians. They said, “We’re in this with you. We will collaborate with you. We will send you patients to put on to your trial.” So I designed the trial that we would document at the trial entry by x-ray and CT scan that there was no detectable metastases in the lung. If we could see it, the patient was not eligible. We would treat the patients. Now, how long do you treat the patients? What do you do? Well, Dr. Fidler’s mouse work, he treated them twice a week for a month, because you can’t just give it once like chemotherapy, because the immune cells renew themselves from the bone marrow. So if you just give one dose in a two- or three-week time, you’re not going to provide a significant number of activated immune cells. So he gave it twice a week for a month and showed that it worked. So I figured, okay, we’ve got to give it twice a week to begin with. How long are we going to treat the patients? Let’s go three months. It was pure pulling out of the air, “Let’s go three months.” So we went twice a week for three months, and during that time, several patients completed therapy, we stopped the therapy, and they started to relapse. And when they relapsed or they had a lesion on the film—there was a lesion on the film—we’ve got to go get it. So in thinking about, okay, this lesion, maybe the lesion—you can see the lesion not because there’s cancer cells there, because you have all these immune cells coming in, so an x-ray doesn’t tell you whether it’s a cancer cell or a normal cell or whether it’s inflammatory response or fibrosis or whatever. Like you can have an old tuberculin lesion in your lung and it shows up on x-ray, but it’s really just fibrosis of the tumor, the lesion that had been walled off by your immune system. So I said, “You know, okay, maybe it’s not really live tumor cells.” So I said, “Okay, we’re going to get the lesion.” I talked to the thoracic surgeon, and the first thoracic surgeon took out the lesion, and he called me. He said, “Well, I got it, but it really looks unusual.” I said, “What do you mean, it looks unusual?” “Well, you know, usually osteosarcoma is invading into the lung and you can’t tell where the tumor begins and the lung is, and they’re always very difficult because they’re invasive. This one was really nicely encapsulated. I just took it out and that was it.” I said, “Okay.” Waited for the pathology. Pathology report came back, said relapsed osteosarcoma. Figured, “Okay.” Another patient, the same thing happened. We stopped therapy and within a short period of time, they showed up with a lesion in the lung. This was a different thoracic surgeon, again at MD Anderson, and says the same thing to me, “I took it out, Genie, but, you know, really—.” Really? Pathology comes back: relapsed osteosarcoma. Another patient relapsed. This was a little girl from New Jersey, and her pediatric oncologist had referred her to me. And he called me and says, “We have a lesion on the—.” I said, “Okay, Michael, have the surgeon take it out and call me, okay?” So he calls me. He says, “Genie, they called me down to the OR. The thoracic surgeon said he had never seen anything like this, so I went in to see it. The lesion was encapsulated. I’ve never seen a pulmonary metastasis from a patient with osteosarcoma look like this.” I said, “Michael, send me the slides.” So I took her slides and the slides from the two other patients and I took them down to one of our pathologists, Dr. Kevin Raymond, and said, “Kevin, don’t tell me this is relapsed osteosarcoma. Tell me if you see anything unusual.” And he looked, he says, “Oh, yeah, but I thought you just wanted to know whether it was osteosarcoma or not.” I said, “Okay, well, tell me what you see. Let’s look at it under the microscope.” He said, “Look. You see this fibrosis around the tumor? You see these dead cells within the tumor? You see this hemorrhage within the tumor? This is all dead cells. This encapsulation looks like tuberculosis.”
Tacey Ann Rosolowski, PhD:
It’s killing it.
Eugenie Kleinerman, MD:
It’s killing it. I took the lesions, I took them back to the lab, and clearly we had the pre-lesion that was removed from these patients and now we had the post-lesion, so we could compare them, looked totally different, and we showed that there were inflammatory macrophages infiltrating into the lesions post MTP and they weren’t there. So my conclusion was that we did have a therapy that was working. Maybe three months wasn’t the right guess. So we went back and amended the protocol to treat for six months. Now, there were all sorts of things that I needed to do to make sure that this protocol could be completed. For example, okay, so we treated twice a week for three months, and then when we extend it, it would be once a week for three months, because I didn’t want to tie the kids to the hospital.
Tacey Ann Rosolowski, PhD:
Now, just to clarify, because you originally said that you were asking adults to be part of this, was this all children, mixed children and adults?
Eugenie Kleinerman, MD:
Mixed. Mixed children and adults.
Tacey Ann Rosolowski, PhD:
Okay, I just wanted to clarify that.
Eugenie Kleinerman, MD:
Mixed children and adults, but the majority turned out to be children.
Tacey Ann Rosolowski, PhD:
Oh, really? Okay.
Eugenie Kleinerman, MD:
Yeah, the majority, and teenagers, although I did have a sixty-five-year-old lady, who is still alive, sarcoma-free.
Tacey Ann Rosolowski, PhD:
Wow.
Eugenie Kleinerman, MD:
How old is she? She must be in her eighties, late eighties now, by now. And she used to come to the pediatric clinic, and when she checked in, people would say, “Are you sure you’re going to pediatric clinic?” “Oh, yes, Dr. Kleinerman’s my doctor. I’m seeing her. She’s in the pediatric clinic.” (laughs) So I had several adults come to the pediatric clinic, which, again, only at MD Anderson would they say, “Yes, you can treat adults in your clinic.” Got the nurses’ okay. They loved having the patients. The treatment was benign. Okay. So to complete the trial, I was going to have to get physicians to refer me the patients to get thirty patients to complete the trial. So, you know, the web wasn’t really—I opened this trial in 1988. It wasn’t really very—I don’t know. People didn’t use the web. So we sent a lot of flyers, I went to meetings, tried to publicize the trial, and that’s how I got physicians to refer. But what I really did not want to do was to have a family required to be here for six months. It was okay if they were from Houston, but, you know, I had patients from New Jersey, I had patients from Pennsylvania, Denver, Colorado. How could you do that to a family? So, knowing that the therapy was really easy to administer, it was an hour infusion in the outpatient clinic, I went to the IRB and said, “Okay, I’d like to have them stay here for a month, I have my research nurse, so they would learn what the side effects are, what you have to do. We’ll educate them. And then minors will go to their referring pediatrician or pediatric oncologist and show them how to administer the drug in the outpatient clinic.”
Tacey Ann Rosolowski, PhD:
Wow.
Eugenie Kleinerman, MD:
Again, totally new concept. I think anywhere else it wouldn’t have worked, because this was really an experimental therapy. This was a Phase 2 protocol. Company said that was fine, and so that’s what we did. We had the patients come here, and said, “You have to stay here for a month. You can stay at Ronald McDonald House.” We had a very nice support from Ronald McDonald House. So they stayed here, they came into clinic. And for the kids that were local, what I would arrange it is, “You can go to school and then come here at the end of the day, we’ll give you your infusion, and then you go home and you’ll have fatigue, and you’ll get up the next morning and you’ll go to school.” I really was very conscious of that, and for these other families that were from out of Houston, they’d come in, they’d be treated twice a week for a month, they’d learn. So they would become experts in MTP therapy, and they’d know you have to get Tylenol beforehand and Benadryl, and if it really becomes the shaking chills, you can get Demerol. So they were very comfortable with the side effects. And then my nurse would go to the office and say to the nurses, “Here’s how you do. Here’s how you take the vial. You put saline in.” And we’d give them a vortex. “You vortex it for five minutes, you dissolve it up, and you run it in in an hour, and in and out.” And it worked extremely well, and so I was able to complete a Phase 2 study with thirty-three patients in three years—
Tacey Ann Rosolowski, PhD:
Wow.
Eugenie Kleinerman, MD:
—which for a rare disease, a single-institution study—and what we showed at the end of the study was that we raised the disease-free survival at one year from 15 percent to 33 percent in the patients that got six-month therapy. In following the data for many, many years—so this trial was completed in 1991, so we’ve got over twenty years of follow-up, survival, 50 percent of the patients are still alive. So even though they relapsed, like the ones that we took to—I’ve kept in contact with some of the patients that were on the three-month and then we took out the lesion. They never had another relapse.
Tacey Ann Rosolowski, PhD:
Wow.
Eugenie Kleinerman, MD:
So something in the immune system is working. We took out what was there, and I don’t know, I mean, but the proof is in the pudding. So half the patients are alive more than twenty-five years later.
Tacey Ann Rosolowski, PhD:
So how has this therapy filtered out to other institutions? And what happened with the acceptance of this data? Was it a rocky road getting people to believe?
Eugenie Kleinerman, MD:
Yes, it was a rocky road, yes. So the physician from New Jersey, Michael Horowitz, was at the time—I think we had talked about this before—in the Pediatric Oncology Group. There were two competing national cooperative groups: the Pediatric Oncology Group and the Children’s Cancer Study Group. So he was in the Pediatric Oncology Group. So when he saw what happened to his patient, he said, “You know, Genie, this is the first glimpse of anything that we’ve had in osteosarcoma. We’re getting ready to write a national Phase 3 trial in newly diagnosed patients. I want you to come and present to the Bone Tumor Strategy Group. I want you to present the data.” So I went and I presented the data, and I was essentially booed out of the room. At the time there was a new drug, Ifosfamide, that an investigator from St. Jude had been doing and showing that you got tumor shrinkage in a Phase 2 trial, so you actually had evidence that the tumor shrank with Ifosfamide. And I was not doing—
Tacey Ann Rosolowski, PhD:
You weren’t looking at that.
Eugenie Kleinerman, MD:
I wasn’t looking at that. Here’s an example. If anything’s effective, it’s going to shrink a tumor, but this isn’t going to shrink a tumor.
Recommended Citation
Kleinerman, Eugenie S. MD and Rosolowski, Tacey A. PhD, "Chapter 9: Designing a Phase II Trial for MEPACT, and the Characteristics of Translational Research" (2014). Interview Chapters. 1405.
https://openworks.mdanderson.org/mchv_interviewchapters/1405
Conditions Governing Access
Open
