Phase 3 trial question

[Rock_Robster]

Hi all, I’ve been asked to consider joining the phase 3 trial for Relatlimab-Nivolumab in previously treated / unresectable stage IV MSS CRC. I note it’s quite an advanced trial running in 100+ centres worldwide, but I’m having trouble locating any results from earlier phases. Wondering if anyone has any further information or insights on this one?

Thanks,
Rob

[CRguy]

Just a quick feedback here Rob
from the following sites, for " Relatlimab-Nivolumab "

https://fightcolorectalcancer.org/trial ... tlimab-fdc

OR

https://www.clinicaltrials.gov/ct2/resu ... ity=&dist=

Do you know the ID Number of the exact trial you are considering ??

Cheers and best wishes buddy
CRguy

[Rock_Robster]

Thanks for the links CRGuy, that’s helpful. It’s the NCT05328908 trial that’s running at 140+ locations.

Cheers,
Rob

[Peregrine]

Hi all, I’ve been asked to consider joining the phase 3 trial for Relatlimab-Nivolumab in previously treated / unresectable stage IV MSS CRC. I note it’s quite an advanced trial running in 100+ centres worldwide, but I’m having trouble locating any results from earlier phases. Wondering if anyone has any further information or insights on this one?

Thanks,
Rob

Hi Rob,

The links in CRguy's post were correct. It's clinical trial NCT05328908 :
https://www.clinicaltrials.gov/ct2/show/NCT05328908

This trial is available in a hospital in Greenslopes, Queensland, Australia, 4102, so it shouldn't be too far away from you there in Brisbane.

The main drug being tested in this trial is the two-drug combo relatlimab + nivolumab (generic name). Its trade name is the Bristol-Myers Squibb (BMS) drug named Opdualag, which has already been approved for melanoma, but not yet for colorectal cancer. The apparent purpose of this trial is to collect data that will help qualify Opdualag for a second indication, namely, late-stage metastatic colorectal cancer.

Safety results from earlier Phase 1 and Phase 2 tests of this drug (Opdualag) can be found in the melanoma literature, but not in the colorectal cancer literature since this CRC trial has only been going on for 6 months and has not yet published any results. (Note: A "Relatlimab-Nivolumab" phase 2 clinical trial with unpublished interim efficacy results for MSS colorectal cancer does in fact exist. This trial is still in progress (still recruiting), but apparently no results for this specific trial have yet been published. It is a single-center trial at Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins with clinical trial identifier NCT03642067.)

There are also some published studies on the two study drugs relatlimab and nivolumab with various preliminary findings and observations vis-a-vis colorectal cancer.

The current NCT05328908 trial is a randomized, open-label Phase 3 trial where Opdualag (relatlimab + nivolumab) is being compared to two drugs that have already been approved for late-stage metastatic colorectal cancer, namely:

• Stivarga (regorafenib)
  
• Lonsurf (trifluridine + tipiracil) also known as TAS-102

In this trial, patients will be assigned randomly to only one of three drugs (1) Opdualag (relatlimab + nivolumab), (2) Stivarga (regorafenib), or (3) Lonsurf (trifluridine + tipiracil). Patients will have no choice in the matter. They will be given whatever option comes up in the randomization.

Apparently, the only real option that a patient has in this trial is to voluntarily drop out of the trial if they don't like the fact that they have now been assigned to one of the two control-group drugs.Thus, there is no guarantee that if you sign up for this trial you will ever be treated with relatlimab + nivolumab. It all depends on the luck of the draw.

Study-drug mechanisms of action
The study drug Opdualag (relatlimab+nivolumab) is a two-drug immunotherapy combination consisting of two monoclonal antibodies with different mechanisms of action:

• Relatlimab (BMS-986016)
  Drug class:  monoclonal antibody
  Anti-LAG-3 :  LAG-3-blocking antibody
  (Lymphocyte Activation Gene-3 blocking antibody)
  
• Nivolumab (Opdivo)
  Drug class: monoclonal antibody
  Anti-PD-1 :  PD-1-blocking antibody,
  (Anti-Programmed Death-1 blocking antibody)

-------------------------------------

I do have some thoughts or reflections about this trial but I wouldn't go so far as to claim that these thoughts constitute "insights" .

• This clinical trial reminds me of the approval timeline for Keytruda (pembrolizumab) -- Keytruda was originally approved just for melanoma and a couple other indications like lymphoma, but after its approval some enterprising oncologists thought of using it off-label for colorectal cancer. Our member here, tchan8888, and others here, were among the first patients who benefitted from this early use of Keytruda in the CRC context. Then after quite some time Merck performed enough clinical trials in the colorectal cancer area to qualify Keytruda formally for solid tumor indications making it formally eligible for colorectal cancer patients.
• In my opinion, Bristol-Myers Squibb is trying the same strategy, hoping to get an eventual formal approval for the use of Opdualag in the lucrative CRC market.
• This trial cannot possibly be set up as a randomized double-blind trial for the obvious reason that the two control-group drugs are pill-based oral drugs while the experimental drug, Opdualag (relatlimab + nivolumab), is an intravenously administered drug.Therefore, this trial has to be set up as an open-label trial.
• I think that the very large number of trial sites launched (currently over 140) can be explained by the fact that there will probably be a lot of drop-outs in the trial when some of the patients find out that they have been assigned a drug like Stivarga (regorafenib) - which many patients find very difficult to handle and not always very effective.

============
Here is an easy-to-read, bird's-eye overview of this trial as described by the Duke Cancer Insitute

What is the Purpose of this Study?

If you choose to join this study, you will:
- Be assigned to get either relatlimab-nivolumab or an existing therapy (regorafenib or trifluridine + tipiracil)
- Get IV infusions of relatlimab-nivolumab every 4 weeks (if assigned) OR take pills of your assigned standard-of-care therapy
- Give blood and urine samples
- Have regular CT or MRI scans

What is the Condition Being Studied?

Colorectal Adenocarcinoma

Who Can Participate in this Study?

Adults who:

- Are diagnosed with with colorectal adenocarcinoma that is metastatic or unresectable (cannot be surgically removed)

- Have had their cancer worsen following prior lines of therapy

Reference: https://dukecancerinstitute.org/index.php/clinical-trial/pro00110299

[Rock_Robster]

Hi Peregrine,

Thanks very much for the information and insights - that’s all extremely helpful. Indeed I would be doing it at Greenslopes Hospital in Queensland, which is extremely convenient as it’s only about 15 mins drive from my house (as opposed to many other trial options which would be an interstate flight).

I’ve got pretty comfortable now with the experimental arm of the trial, and interesting to see the melanoma history and Keytruda analog. My oncologist(s) are both pretty confident there’s unlikely to be a better I/O (PD-1 combo) trial option here in the next 1-2 years, so good to go for this one. Indeed my main concern now is with the control arm. My oncologist is keen that I don’t have Lonsurf as, (1) it would exclude me from most future trials, and (2) if I did I’d want to do it with Avastin, which wouldn’t be available under the trial protocol. The alternative control drug (regorafenib) is not normally available here in Australia (actually to be accurate, it’s approved for use but not subsidised by the government or covered by any insurance so the cost is prohibitive for most people), but it is available via this trial. So I could get rego which in a way would effectively be a ‘bonus’ line of treatment for me and wouldn’t rule me out of future lines and trials. However I’m concerned because on the median it’s a pretty disappointing drug with a famously intolerable side effects profile (as you point out). If I was to do rego I’d prefer to do a dose escalation protocol (ie ReDOS), but again this wouldn’t be available under the trial regimen (160mg is protocol dose).

I appreciate I always have the option to drop out if I get randomised to the control arm (as it’s not blinded) as you point out, but my oncologist was pretty disapproving of this path so if I enrolled in the trial and got the control I think I’d have to be prepared to at least give the rego a go for a few cycles, and if it’s intolerable then I withdraw consent then on that basis.

The alternative of doing the liver SABR now remains on the table, but it’s a little complex as this would probably leave me without measurable disease (as the lung things are sub-cm), thus not qualifying for any trials. Hence I’d be left with only standard of care chemo to try to control the lung mets, plus anything subclinical/microscopic.

So it looks like the plan from here is to go through qualifying for the trial (of course I still may not qualify for any number of reasons), and go from there. Good to know that I seem to have quite radiosensitive disease and liver SABR remains an option if I have progression on either trial drug or the control, and I always have standard of care chemo as backup while I work on other options (actually I technically haven’t progressed on any lines of chemo yet, which I guess is a little unusual for 4 years post stage IV diagnosis).

Thanks again for all the advice, links and insights. Further thoughts from anyone always welcome.

Cheers,
Rob

[Peregrine]

Hi Rob,

Thanks very much for the update!

If you think you might be eligible for this trial, could you let us know a little ahead of time so that we can provide some feedback? I think there are some important protocol-based issues that need to be discussed during your Informed Consent meeting before you sign the Informed Consent document. This is so that there are no surprises once you commit yourself to the trial.

Clinical trials are highly controlled studies, and volunteers need to understand what they will be getting into. These trials are intended for collecting protocol-based data that will support the company's evidence-based application for regulatory approval of their experimental drug. These trials are not primarily designed to give patients one last chance to find a regimen that works.

To phrase it a bit differently, clinical trials are not basically humanitarian or compassionate activities. They are more economic in nature and serve to support the business plans of the companies that are developing the new drugs.

Because of this I think that volunteers need to be careful and do all their homework in advance of signing up, and to understand the trial's protocol requirements thoroughly. That's just my personal opinion; others may disagree.



,

[Rock_Robster]

Thanks Peregrine. I have my Informed Consent meeting with the local trial lead this Friday (21st), after which they will conduct scans, bloods and tumor tissue sampling to determine my eligibility. I’m always very open to issues that the group thinks I should cover off with the trial doctor!

Thanks again,
Rob

[beach sunrise]

Hey RR, I don't have anything to offer besides I pray it goes well. I''ll be thinking about you and looking for updates.

[Peregrine]

Some thoughts...

1.How long do you expect treatment to last?
- Until first Grade 3 (serious) or Grade 4 (life threatening) adverse event?
- Until there is evidence of progression while on treatment?
- Until the standard dose can no longer be tolerated?
- Until the end of the study (2025)?

2. Are chemo breaks / pauses in treatment allowed?

3. If the drug works well for you, will you be able to continue with it after the end of the trial?(probably not, see red-font notice in trial protocol)

4. Who will be in charge for the duration of the trial?
-What role does the trial coordinator have?
-What specialty / expertise does the trial coordinator have? What kind of doctor is he?
- What role does your local oncologist have for the duration of the trial?
- What role does your multidisciplinary team have for the duration of the trial?
-Will your team have much power to make decisions when the trial is ongoing, or is everything going to be dictated by the trial protocol?

5. Who will you be meeting with on a regular basis during the trial -- your local oncologist, or the trial coordinator?

6. Are you allowed to take supplements or alternative treatments during the trial?

7. Where are the clinical trial test results kept?
- Are they going to be accessible by the patient in the patient's portal?
- Are the results made available to the whole team?
-Will the clinical trial team have access to all previous tests / scans, or only the results appearing after the trial's baseline.

8. Efficacy - how often are scans done?
- Are scans done on a fixed, inflexible shedule .. every 6 months or so?
-Can your local oncologist order scans or tests that are not listed in the trial's protocol?
- Can a patient request a different kind of scan (PET/ CT or MRI)?
- Can a patient request a second opinion on scans done during the trial?
-What if there are differences of opinion about scan interpretation?

9. Clarification? "tumor tissue sampling to determine my eligibility" ... Tissue from which tumor? By which method -- by needle biopsy??? . Or is it a sample from the original primary tumor still in long-term storage?

10. Also, what kinds of panels will be included in the blood tests? How comprehensive, how extensive? how many cancer biomarkers assessed, etc.? Will they be testing CA 19.9? Will the be doing any ctDNA tests for circulating tumor DNA, for example. Will there be any panels to assess general level of systemic inflammation, etc.? Are these tests only for establishing eligibility? If so, then when will they be doing comprehensive testing to establish a good study baseline, and what tests will be included in that baseline?

11. Timeline? How long will it take them to determine your eligibility? If you are deemed eligible, then how long will it be before you can start treatment?

12. Informed consent in Australia.

https://www.bmj.com/content/324/7328/39

Summary points

In the past decade both English and Australian courts have adopted a more patient centred standard in deciding what risks doctors must disclose to patients

Professional bodies have issued guidelines to help doctors inform their patients

Yet in Australia many doctors still do not understand their legal duties and many are being held liable for their failure to inform

[Rock_Robster]

Thanks Peregrine and all for the input and well-wishes!

Funny twist - saw the trial doc today and concluded that I don’t yet qualify for the trial. Although I’ve been going for 4 years now, I’ve never progressed on any lines of chemo (I stopped FOLFIRI at my last resection), and I’ve never had a targeted therapy (such as bev). Recent progression on at least one early line plus prior treatment with either a VEGF or EGFR inhibitor are both qualifying criteria.

So now I’m back to either maintenance chemo (eg cap + bev) or liver SABR next. Perhaps time to get some updated scans to help make the call.

Either way I suppose it’s “good” news in a strange way - these trials will hopefully always be around and hopefully also get better with time. The doc was optimistic about the outlook for more immunotherapy trials access in future. We will see.

Thanks,
Rob

[Peregrine]

Hi Rob,

I'm sorry to hear that your clinical trial possibility evaporated so quickly. Maybe there will be better opportunities coming along soon. You can search for them yourself with the MSS CRC Trial Finder below.

• The opportunity: If your tumor is MSS (not MSI-H), you can find a clinical trial for late stage CRC here:
  
  Late Stage MSS CRC Trial Finder
  "The current data are limited to MSS (microsatellite-stable) and stage IV CRC patients. Then list of trials curated here is sourced from the ClinicalTrials.gov website."
  
  Reference:
  https://fightcolorectalcancer.org/resources/late-stage-mss-crc-trial-finder
  ======================================
• The dilemma: Around 10% of all CRC cases are MSI-H and have relatively good response to immunotherapies like checkpoint inhibitors. However, the other 90% of CRC cases -- i.e., the MSS cases -- have shown little or mixed/mediocre response to immunotherapies. Thus, the big problem for MSS CRC patients is to try to find an immunotherapy combo that has more than just a mediocre response.
  
  In the context of clinical trial NCT05328908, both of the active components are checkpoint inhibitors:
  
  
  
  • relatlimab --> Anti-LAG-3 :  LAG-3-blocking antibody
    
  • nivolumab  --> Anti-PD-1 :  PD-1-blocking antibody
  So this is the dilemma: These drugs are checkpoint inhibitors, but it turns out to be rather difficult to get these kinds of drugs to work well with MSS patients. So, clinical trial NCT05328908 is yet another attempt to get these types of immunotherapy drugs to work well in this context. Whether this combo will work better than others in the past, only time will tell.
  
  To me, this doesn't look like the magic bullet that everybody has been looking for over the past decade or so. It seems to me to be just another effort to "leave no stone unturned" in the long search for something better for MSS patients.

Some references below:
======================================
"Despite the great success of ... [Immune checkpoint inhibitors] ... on MSI-H CRC, the majority of clinical trials of Immune Checkpoint Inhibitors (ICIs) in MSS CRC have ended in failure."

"Clinical Application of Adaptive Immune Therapy in MSS Colorectal Cancer Patients (2021)"
Reference: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548603/

======================================

"... Microsatellite stable (MSS) colorectal cancer has long been considered resistant to immunotherapy..."

"Metastatic disease sites may predict for the response or resistance to checkpoint blockade, with liver metastases emerging as a strong predictive biomarker of lack of benefit from PD-1 targeting, even with combination therapies."

Reference:
Targeting MSS colorectal cancer with immunotherapy: are we turning the corner?  (2021)
https://pubmed.ncbi.nlm.nih.gov/34030532/#
======================================