PDIGREE: An adaptive phase III trial of PD-inhibitor Nivolumab and Ipilimumab (IPI-NIVO) with VEGF TKI Cabozantinib (CABO) in Metastatic Untreated RCC (Alliance A031704). -Tian Zhang

June 7, 2020

PDIGREE is a novel adaptive frontline immunotherapy study which upon completion will help answer many important questions regarding treatment duration, when to combine VEGF therapy with IO therapy, and which patients benefit most from IO-VEGF combination upfront vs. sequential therapy. This trial is actively enrolling patients at all National Clinical Trials Network (NCTN) study sites. The primary investigator of the PDIGREE trial, Tian Zhang, details the adapted phase III immunotherapy study in metastatic renal cell carcinoma treatment. Patients enrolled in the trial are treated with a combination of ipilimumab and nivolumab every three weeks for four cycles. Following this induction period, patients with a complete response proceed with maintenance nivolumab, and those with a partial response are randomized to nivolumab or nivolumab and cabozantinib, with a primary objective of three-year overall survival for the randomized cohort. Dr. Zhang also discusses the protocol modifications that were made to the trial following the onset of the COVID-19 pandemic.  


Tian Zhang, MD, Assistant Professor of Medicine in the Division of Medical Oncology and the Department of Medicine and a member of the Duke Cancer Institute

Alicia Morgans, MD, MPH Associate Professor of Medicine in the Division of Hematology/Oncology at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

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Alicia Morgans: Hi. This is Alicia Morgans, GU medical oncologist and Associate Professor of Medicine at Northwestern University. I am so excited to have here with me today, a friend and colleague, Dr. Tian Zhang, who is an Assistant Professor of Medicine at the Duke Cancer Institute and also the national PI of the PDIGREE trial that's being run through the Alliance Cooperative Group. Thank you so much for being here, Tian.

Tian Zhang: Oh, It's my pleasure, Alicia.

Alicia Morgans: Wonderful. So can you tell us a little bit about the PDIGREE trial? This is a trial in kidney cancer patients. It's been going on for a little bit of time now, continuing to accrue across the country.

Tian Zhang: Sure. Yes. This is our adaptive Phase III trial and first-line treatment of metastatic clear cell kidney cancer, intermediate core risk by IMDC criteria, but everyone is treated with ipilimumab nivolumab for up to four cycles upfront. And then depending on their three-month responses, we adapt the treatment to their response. So complete response patients receive nivolumab alone. Patients who develop progressive disease will receive cabozantinib alone, and then patients who have a partial response or stable disease, we're randomizing those patients to either nivolumab or the combination of nivolumab with cabozantinib. And the objective, the primary endpoint of this study is really to look at the three-year overall survival rate for the randomized cohort to try to extend that with the early addition of cabozantinib in combination with nivolumab. And so the trial has been ongoing, as you said for the past year. It's been open since May of 2019.

Alicia Morgans: Wonderful. And I think I particularly like this study because I think it gives a great option for these patients with metastatic clear cell kidney cancer to really hopefully find the right amount of treatment for them to really respond to their response or their non-response to the therapy being effective or less than effective or intermediately effective, which is such a really creative and thoughtful way to run a trial. That being said, I'm sure that it's hard to go through all the things that you're going through. I mean, many patients, clinicians might be having questions at this point in time about how enrollment and participation in the trial is actually being affected by the COVID-19 pandemic that is hitting the country. What have you done to really address those concerns and to continue to treat and enroll patients despite that?

Tian Zhang: Yeah, no. That's a really great question. And very early on, the NCI made a push before all the cooperative group trials to make protocol accommodations for COVID-19. In March of 2020, we made a host of protocol modifications. We allowed for the lack of physical exams, for example. If patients were doing remote visits, we allowed for external labs to be collected and then for these telehealth visits to occur. And then we made modifications to make sure that patients could get their scans in time. So we opened up the window for the 12-week scan to plus or minus two weeks. And then finally we made accommodations for quality of life surveys as well for these patient-reported outcomes to be obtained through telephone visits instead of in-person visits.

So I agree with you that in this COVID-19 pandemic, many of us are adjusting our practices and our clinical trial protocols are trying to accommodate for those practice changes. And hopefully, these protocol changes are actually helpful for sites to continue to accrue patients. In PDIGREE, we were initially moving right along and we still are. We've seen a drop of a couple of patients per month, but we certainly are continuing to actively accrue. And if the sites have this open across the NCTN network, I'd love to hear from them as they continue to screen patients for PDIGREE.

Alicia Morgans: I think that's great advice. And really, I have to say that the accommodations that you and the team at the Alliance have put forth really seem to reflect the changes that we're making in our practices and add that flexibility to allow patients to feel safe, to allow clinicians to do what they are probably doing in their practices anyway. Allowing external labs is actually a pretty big deal I would imagine, through the Alliance Network, because for clinical trials, generally, we always use approved laboratories. So that is a huge accommodation, I think, and something that is so responsive to the needs of patients and clinicians at this time.

So I'm hopeful that that small blip that we saw in the decreased enrollment by a patient or two a month is something that as we become more comfortable living with COVID-19, which is something that I think we're all going to have to do, that people will start upping those numbers again. Because, again, this adaptive design is really meant to minimize toxicity in patients who are responding and certainly very quickly provide more disease control options for those patients who are either not responding sufficiently or whose disease is progressing despite the treatment. So rapid adaptation within a trial, and then these constellations in terms of loosening restrictions, it's really, it's phenomenal. And I am sure that enrollment will pick up. Speaking of that, how is enrollment doing at this point?

Tian Zhang: Yeah. So over the past year, we've accrued about 140 patients and we're continuing right along. So I think it's at a good pace. Certainly, we planned for enrollment over at least three years. And so we're still sort of in the early phase of that. And I'm hoping as, you're right, as we're becoming a little bit more comfortable reopening and making sure that patients continue to be safe, but their cancer doesn't stop growing for COVID-19. And I'm hoping that we'll still be able to enroll and that these sites will still have PDIGREE as an option for their patients. In the context of the recent changes in the first-line landscape, there we have seen significant activity of the cabozantinib nivolumab combination as well.

There was a press release that showed us that from the CheckMate 9ER study that showed us that cabozantinib/nivolumab was superior to sunitinib. And so we know this to be a very effective strategy and treatment combination. I'd love to see that improve survival outcomes and also complete response rates, really, where ipi/nivo is the combination with the highest complete response rates. And hopefully, the randomization to cabozantinib/nivolumab will also augment that CR rate. So we'll see it's an art project in the making of this very large trial as we go along.

Alicia Morgans: Yes. And when you're doing this at an adaptive form, it's definitely going to require a lot of patients. So I encourage patients and clinicians who have patients who may be candidates for this trial to really seek out those sites where they can get this adaptive design because, as you said, we are seeing activity in the cabo/nivo space, and we're really trying our best to identify those patients who are adequately treated with ipi/nivo and then can just continue nivolumab or those patients who need that adaptation and alternative approach so very, very exciting. So as clinicians are identifying patients, as patients are seeking out care for themselves, how can they find out where they might be able to receive treatments on the PDIGREE trial?

Tian Zhang: Our sites are open and they're listed on clinicaltrials.gov. But if there are any patients who are looking for a site close to them, I'm always happy to hear from patients and sites to make sure that we're finding a place close to where they live.

Alicia Morgans: Wonderful. Well, thank you so much for sharing the status of the PDIGREE trial. The adaptations that you and the team have made in terms of the COVID-19 pandemic and the way that you are really trying to keep patients safe, keep the trial enrolling, and match what we're doing in clinical practice to really continue the progress that you're making. And we wish you and the team a lot of success. As we understand this really kind of new attempt at this adaptive design, I think that's going to be so important to patients. And I thank you so much for your study and for your time today.

Tian Zhang: Oh. We really appreciate UroToday and you highlighting the PDIGREE trial. Thanks so much.