AntiCTLA-4 + antiPD-L1 trial (Wolchok) Immunotherapy UPDATE

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Maia
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AntiCTLA-4 + antiPD-L1 trial (Wolchok) Immunotherapy UPDATE

Postby Maia » Wed May 28, 2014 2:29 pm

FYI
There is a 'small' trial that is equally or even more interesting than the ipilimumab + Nivolumab one from Bristol-Myers Squibb.
Similarly to that one, it involves two agents that target CTLA-4 and PD-1/PD-L-1. But it happens that these two agents are not from 'big' pharmas, so the trial is small. It's only available in Boston and New York.

The following trial is currently recruiting patients:

Phase I trial of tremelimumab (anti-CTLA-4) and MEDI4736 (anti-PD-L1) used in combination for patients with advanced solid tumors NCT01975831: http://clinicaltrials.gov/ct2/show/NCT01975831. This trial is sponsored jointly by the CRI/Ludwig Clinical Trials Network. Patients with advanced solid tumors, including colorectal cancer, are eligible for the trial.


So, the tremelimumab is similar to ipilimumab and MEDI4736 is similar to Roche/Genentech's MPDL3280A (as MPDL3280A, it targets PD-L1, the ligand, instead of nivolumab (anti-PD-1) that targets the protein)

The remarkable aspect is that Dr Wolchock is the study chair investigator and that it's sponsored by the leading institutions in immunotherapy for cancer:the Ludwig Institute for Cancer Research and the Cancer Research Institute.
It's probably less 'crowded', since it's a little difficult to choose, if you don't understand a bit more what's going on there ('just phase I', 'never heard of those drugs', 'it's not from a big company', etc.)

anti-CTLA-4 = anti-Cytotoxic T-Cell Lymphoma-4 Antigen
Last edited by Maia on Tue Jun 03, 2014 5:26 pm, edited 2 times in total.

Busymamaof3
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Re: Other anti-CTLA-4 + anti PD-L1 trial (Wolchok) Immunothe

Postby Busymamaof3 » Thu May 29, 2014 3:22 pm

Thanks for posting! I emailed them for more information....looks potentially worth the travel involved.
Dx Stage IV CRC 8/12, 40yrs old
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Folfox alone 4 rds
HIPEC/CRS 2/13/13
PT3N1cM1
Back on Folfox 3/12 - 4/23/13
It is back 8/23/13
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juliej
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Re: Other anti-CTLA-4 + anti PD-L1 trial (Wolchok) Immunothe

Postby juliej » Thu May 29, 2014 4:42 pm

Thanks, Maia! This is a very interesting phase 1 study. The locations are Boston, Buffalo, and NYC. It's amazing that Dr. Wolchok is the lead investigator and also who is sponsoring it (Ludwig and CRI). I love Dr. Wolchok's passion for immunotherapy! :D
Stage IV, liver/lung mets 8/4/2010
Xelox+Avastin 8/18/10 to 10/21/11
LAR, liver resec, HAI pump 11/11
Double lung surgery + ileo reversal 2/12
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Busymamaof3
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Re: Other anti-CTLA-4 + anti PD-L1 trial (Wolchok) Immunothe

Postby Busymamaof3 » Thu May 29, 2014 6:34 pm

I was told there is a long wait list and I am better off staying in my spot in line for the other one.... So anyone interested needs to get your name in soon.
Dx Stage IV CRC 8/12, 40yrs old
3 kids under 10
10/5/12 1 met to liver
folfox w/avastin 4 rds
Folfox alone 4 rds
HIPEC/CRS 2/13/13
PT3N1cM1
Back on Folfox 3/12 - 4/23/13
It is back 8/23/13
FOLFORI 9/13-1/14 cea up
Folfox 1/13
Hipec w crs #2 2/27/14

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Maia
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Re: Other anti-CTLA-4 + anti PD-L1 trial (Wolchok) Immunothe

Postby Maia » Thu May 29, 2014 7:10 pm

Busymom, it's wonderful that you have checked that, and that you're letting know this, to all who are in need here... that's just so great.
I don't know if it means something but wanted to tell you that I feel that *your* plan, that we've talked about, it IS a good one. Hang in there! : )

I so wish clinical trials were designed around patients' needs, no the other way -people have to work like crazy to find a window of opportunity, a 'match'... it's so frustrating, it takes a lot of time, energy... I do know that. I don't know how someone could embark in such task only when he/she has ran out of options... In this video, during the first minutes, Dr Silvia Formenti talks about other metastatic cancer (breast) but she is very aware that the situation is even *worse* for other metastatic solid tumours (say, colon/rectal). She also is frustrated because drugs that are approved for others cancers are not simply tried when one knows a patient's tumour *has* the right markers for that (I'm not saying that that would be a cure, but why don't use that in the meantime, instead of a 'general', non specific agent/combo, usually so toxic and with so little benefit). Since she's articulated and I'm not, better if you hear her, it's only the first 5 minutes... she's a little frustrated and very honest, something that I appreciate in a doctor talking in front of colleagues: https://www.youtube.com/watch?v=8FNkdNCGzVA
Sorry for the rant. I get specially frustrated at the end of certain days : (

On a side note: I said that the agents in this trial are not from a big pharma. Well, they might be --I found that MedImmune LLC is the biologics research and development arm of AstraZeneca; it just has been said that "This year 2014 marks the ASCO "debut" of AstraZeneca (AZN_) to the checkpoint inhibitor race" (the contenders until now were Roche/Genentech, Bristol-Myers Squibb and Merck).
So.. not so little trial.

juliej wrote: I love Dr. Wolchok's passion for immunotherapy! :D

Me too, Julie! People like him and some others out there give me so much hope!!

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Maia
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Encouraging data for MEDI4736 (PD-L1)

Postby Maia » Tue Jun 03, 2014 5:17 pm


Updated. Report from ASCO meeting June 3rd 2014
, about the anti-PD-L1 (MEDI4736), with a reference to the other agent used in this trial, the anti CTLA-4 (tremelimumab)

(it's a press release from the company that makes the drugs, so take it as that : )


    AstraZeneca’s MedImmune Presents Encouraging Immunotherapy Data at ASCO 2014



    Data support rapid progression to Phase III development for MEDI4736 (PD-L1)

    June 3, 2014

    CHICAGO — MedImmune, the global biologics research and development arm of AstraZeneca, presented results today from its novel investigational immunotherapy portfolio, focusing on MEDI4736, at the American Society of Clinical Oncology (ASCO) 2014 Annual Meeting. Overall, studies demonstrated durable clinical activity and tolerability for MEDI4736 across a range of tumor types.

    This announcement follows the recent progression of the first Phase III study for MEDI4736, an investigational, engineered, human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). Signals from PD-L1 help tumors avoid detection by the immune system. It is believed that by targeting PD-L1, MEDI4736 may block this ligand from sending out signals to T-cells to ‘ignore’ tumor cells, thereby countering cancer’s immune-evading tactics.

    Multiple sets of data were presented from MEDI4736, including dose-escalation data, dose expansion data, and an analysis of pharmacokinetic data.

    MEDI4736: Four Data Sets Point to Early Clinical Activity and Tolerability

    In a Phase I dose-escalation study (Study 1108) of MEDI4736 in 27 patients with advanced solid tumors, reduction of tumor burden was seen at multiple dose levels in as early as six weeks. Clinical activity was maintained for at least one year, with 19 percent of patients achieving a partial response and 39 percent of patients achieving disease control. There was a very low frequency of drug-related serious adverse events, and no dose-limiting toxicities were observed. The tumor types included in the escalation phase of this study were non-small cell lung cancer (NSCLC), melanoma, colorectal cancer and renal cell cancer (Lutzky, abstract 3001: A phase 1 study of MEDI4736, an anti–PD-L1 antibody, in patients with advanced solid tumors).

    Treated patients who had advanced NSCLC were separately reported in a poster discussion at ASCO. Data from ~150 NSCLC patients found no treatment discontinuations for toxicity, drug-related colitis of any grade, or grade three or four pulmonary toxicities. An early signal of clinical activity was observed in patients with both squamous and non-squamous NSCLC treated with MEDI4736 (Brahmer, 8021).

    Data from the dose expansion phase in ~350 patients provided further information on the clinical activity and tolerability profile of MEDI4736, showing early evidence of clinical activity in multiple tumor types, including NSCLC, squamous cell carcinoma of the head and neck (SCCHN), pancreatic cancer, gastroesophageal cancer, and cutaneous melanoma (Segal, abstract 3002).

    Additionally, an analysis of pharmacokinetic (PK) / pharmacodynamics (PD) data indicated a very low incidence of immunogenicity (2 of 196 patients) with no impact on PK or PD at the phase II and III dose of 10 mg/kg. Furthermore, the study demonstrated dose-dependent PK and soluble PD-L1 suppression in patients with solid tumors (Fairman, abstract 2602).

    “The data presented at ASCO reinforce the importance MEDI4736 plays in our immuno-oncology portfolio, and more broadly, the potential role it has to help in transforming cancer therapy, alone and in combination with other treatments,” said Dr. Edward Bradley, Senior Vice President, R&D and Oncology iMED Head, MedImmune. “In our Phase I studies, MEDI4736 has demonstrated encouraging clinical activity and tolerability profile across a range of tumor types. We look forward to seeing further data on this molecule as part of current Phase III program, as well as the numerous combination trials underway.”

    Accelerated development of Novel Combinations, Additional Immunotherapy Studies

    There are two ongoing combination studies exploring different doses and schedules of tremelimumab (CTLA-4) + MEDI4736, one in multiple tumor types through a collaboration with the Cancer Research Institute/Ludwig Cancer Research and the other in NSCLC. MedImmune provided a preliminary status update of the Phase I MEDI4736 + tremelimumab combination study in NSCLC at the AstraZeneca analyst and investor briefing on June 2, 2014 at ASCO. Dose escalation is continuing with no maximum tolerated dose defined to date. Early, preliminary clinical activity has been observed with this combination in patients with advanced NSCLC.

    MEDI4736 and tremelimumab target non-redundant pathways to fight cancer, working at different checkpoints to engage the immune system to possibly overcome cancer’s immune-evading tactics. In one mouse study, combining agents that target PD-L1 and CTLA-4 produced synergistic effects and led to complete tumor regression.

    MedImmune is also exploring tremelimumab as monotherapy in a pivotal study for malignant mesothelioma, a patient population with a very high unmet need. Updated Phase II data from an investigator-initiated trial exploring tremelimumab in malignant mesothelioma was also presented at ASCO.

    MedImmune data at ASCO 2014 continue to highlight the company’s immunotherapy portfolio. Among the 10 abstracts presented by MedImmune, data include:

    • Combination therapies: recruitment is ongoing for additional combination treatments. This includes a Phase I study of MEDI4736 in combination with dabrafenib and trametinib or trametinib alone in patients with unresectable or metastatic melanoma (Gordon, abstract TPS9108).
    • MEDI3617: a Phase I dose-escalation study investigated MEDI3617 alone and in combination with carboplatin/paclitaxel, paclitaxel or bevacizumab across a variety of tumor types in adults with advanced solid tumors, and researchers observed clinical activity along with an acceptable tolerability profile (Hyman, abstract 3012).
    • MEDI-551: a Phase II study is ongoing to evaluate tolerability of MEDI-551 among 124 patients with relapsed/refractory chronic lymphocytic leukemia (Gladstone, abstract 3028).


(For those interested in find the other abstracts mentioned here, put the abstract # in the ASCO search engine: http://abstracts.asco.org/144/CatView_144_S.html

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Maia
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Re: AntiCTLA-4 + antiPD-L1 trial (Wolchok) Immunotherapy UPD

Postby Maia » Wed Oct 01, 2014 7:59 am

Information from this past weekend, Spain ESMO 2014
http://uk.reuters.com/article/2014/09/2 ... D420140927


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