NorthWest Biotherapeutics Inc (NWBO)

[sentiment_stocks]

Regarding RECIST and the P1 Direct Trial…

There has been quite a bit of discussion both on I-Hub and YMB about RECIST and Standard of Care.

Below is a link to MDAnderson’s protocol for the open label P1/2 trial.

http://utm-ext01a.mdacc.tmc.edu/Dept/PROT/clinicaltrialswp.nsf/Index/2013-0160?OpenDocument&ExpandSection=3#_Section3

What’s great is that this trial - which the company has told us they’ve collaborated closely with the FDA to design - will:

Evaluate changes in tumor burden and the potential for the observation of tumor response criteria such as RECIST 1.1 and immune response related criteria (IRrC) as well as pathological examination of tumor biopsies.

It looks like MDA, NWBO and the FDA have covered everything there. So I think the trial is safe in its choice of criteria.

What’s also interesting about the updated Direct protocol (modified on 2/2/15) is that there is a Part 2 to the P1 trial. I was concerned about what happens to the patients after they’ve received all their injections in one tumor. Well when one looks at the “Inclusion Criteria” at the 11th inclusion, you can see that in Part 2 (not Phase 2), those patients with multiple tumors will move on to receive additional doses in up to 3 tumors. My guess is, some of those earlier Phase I DCVax-Direct patients have already moved into Part 2. Anyhow, I just think that’s terrific because those P1 patients will be able to continue to benefit from Direct, and under the treatment conditions (multiple injections) seen from the pre-study trials with animals.

Here's the relevant quote:

11) Sufficient doses of DCVax-Direct available for injection (as per Section 5.7). In Part 2, between 1 and 3 lesions will be injected with 2 million cells each, meaning that subjects with 3 lesions will require 3-fold more doses available for eligibility. a)1 injectable lesion: 6 injection visits with 2 million DC injected into one lesion; b) 2 injectable lesions: 6 injection visits with 2 million DC injected into each of 2 lesions [4 million DC per visit]; c) 3 or more injectable lesions: 6 injection visits with 2 million DC injected into each of 3 lesions [6 million DC per visit].

So we can see from the above first quote from the MDA protocol for Direct is that our carefully designed trial will be using four criteria to evaluate the results…


- Tumor Burden
- RECIST 1.1
- IRrC (Immune Response Related Criteria)
- Pathological Examination of tumor biopsies

For a detailed look at the differences between RECIST 1.0 (from 2000), RECIST 1.1 (from 2009) and IRrC, you can visit this website.

http://www.irrecist.com

Here's a quick snippet for those not inclined to read the whole thing...

RECIST 1.1 has its shortcomings for targeted immunotherapy in oncology. Using RECIST 1.1 in immunotherapy trials would lead to declaration of progressive disease (PD) too early, when the treatment effect is not yet fully evident. RECIST also neglects the importance of the ‘flare effect’ - pseudo-progression effect within the so-called flare time window.

Immune related Response Criteria (irRC) based on WHO criteria were published with an aim to provide better assessment of the effect of immunotherapeutic agents. With this poster we introduce irRECIST based on RECIST 1.1, irRC and Nishino et al., 2013 findings. Our aim is to define criteria that better capture antitumor activity and reduce irRC criteria ambiguity.

Consistent implementation of irRECIST by both investigators and blinded independent readers will help reduce site: central discordance.

And for another careful look at Immune Response Related Criteria, this abstract on Yervoy (ipilimumab) from 2009 may help.

http://clincancerres.aacrjournals.org/content/15/23/7412.full.pdf

It’s apparent that the issues of using only RECIST in measuring immunotherapy’s effects have been realized for several years now, as this abstract dates back to 2009.

The discussion portion at the end even states…

The apparent increases in tumor burden that sometimes precede responses in patients receiving immune therapy may reflect either continued tumor growth until a sufficient immune response develops or transient immune-cell infiltrate with or without edema.

and…

Clinical investigation of cancer immune therapies is hampered by the absence of response criteria that can comprehensively describe all patterns of antitumor activity associated with such agents. This was evidenced by reported clinical experiences with cancer vaccines that induced responses of SD or PR (11, 12). [color=red]In these studies, some responses originally evaluated as SD [stable disease] or PD [progressive disease] showed evidence of subsequent tumor regression[/color] (11), whereas others showed “mixed responses,” consisting of regression in some lesions while others remained stable, progressed, or appeared simultaneously (12). Whereas such patterns have been described by many investigators, the clinical significance of these observations has not been adequately studied due to the lack of suitable response criteria to capture the patterns. Overall, such observations indicate the need for novel criteria in the evaluation of responses to immunotherapeutic agents.

Here's the conclusion:

Systematic criteria, designated immune-related response criteria, were defined in an attempt to capture additional response patterns observed with immune therapy in advanced melanoma beyond those described by Response Evaluation Criteria in Solid Tumors or WHO criteria. Further prospective evaluations of the immune-related response criteria, particularly their association with overall survival, are warranted. (Clin Cancer Res 2009;15(23):7412–20)

I think all longs will appreciate that fact that the IRrC criteria is a set of published rules that are made up just to assess the effects of “immunotherapeutic agents.” And RECIST 1.1 has been modified in part as well, I’m sure, for the very reasons that immunotherapies are requiring a different evaluation approach.

In the end, the criteria chosen to evaluate the open label protocol for Direct, appears to be well thought out and is covering all angles. Enough unsubstantiated FUD already.