R1507 IGF-R1 Monoclonal Antibody in Sarcoma

[Fictional]

I came across this trial in recurrent and refractory sarcomas. This monoclonal antibody seems to have a good safety profile and promising effects in refractory sarcomas. One large multi-center trial has closed, but there are ascending dose trials for children, adolescents, and adults at several U.S. sites.

There are 3 lines of evidence that suggest IGF inhibition may be effective in alveolar soft part sarcoma:

1. IGF is chronically activated in ASPS
AACR 2008 Abstract (Olga posted elsewhere, but I'll repost to make it easier to find)
Carolyn J. Hoban, Daffyd Thomas, Dina Lev, R. Pollock, Laurence H. Baker. University of Michigan, Ann Arbor, MI, MD Anderson Cancer Center, Houston, TX
Objectives. IGF-1R expression is important for cell growth, proliferation, survival and progression of cancer. Expression of IGF1R and its ligands have been demonstrated in sarcoma subtypes, such as rhabdomyosarcoma, osteosarcoma, small blue cell sarcomas and synovial sarcoma. With the current clinical development of candidate drugs that target the IGF1 axis, the role of IGF1R in sarcoma subtypes is a major focus of research. We examined histological subtypes of sarcomas and compared IGF1R activation status in sarcoma subtypes. We undertook this study to determine the level and activation status of IGF1R pathway in clinical specimens of sarcoma subtypes in order to develop markers predictive of response or resistance to IGF1R therapies in future clinical studies.
Methods. Frozen human sarcomas were obtained and protein was extracted with protease and phosphatase inhibitors. Total and phospho-IGF1R levels were determined using capture ELISA and confirmed by immunoblot. The activation index (amount of phosphorylated to total IGF1R) was determined for each clinical specimen. Western blot analysis of effectors downstream of IGF1R was performed. Sarcoma subtypes were confirmed in clinical specimens by molecular diagnostic assays.
Results Among the sarcoma subtypes assayed, Ewing's sarcoma family of tumors (EWS), alveolar soft part sarcoma (ASPS), malignant peripheral nerve sheath tumor (MPNST), synovial sarcoma (SS), osteosarcoma (OS), myxoid liposarcoma (MLPS), leiomyosarcoma (LMS) and malignant fibrous histiocytoma (MFH), there was significant heterogeneity of IGF1R expression. The highest levels of IGF1R were found in MPNST, OS and MLPS. However, LMS, ASPS, and OS had lower levels of phospho-IGF1R than MPNST, synovial sarcoma, MLPS, and EWS. While OS tumors expressed high levels of IGF1R, the fraction of activated phospho-IGF1R was low. In contrast, MPNST, ASPS and EWS exhibited a state of chronic IGF1R activation. The activation index of IGF1R is highest in EWS. Ewing's sarcoma clinical specimens with the highest levels of IGF1R activation were also associated with activation of the mTOR/S6K1 axis.
Conclusion. These results demonstrated the heterogeneity of IGF1R levels and activation of signal transduction pathways among sarcoma subtypes. We show evidence of activation of IGF1R in clinical specimens of EWS, ASPS and MPNST sarcoma subtypes. The activation index, along with IGF1 ligands and binding proteins, will be incorporated into translational science of future clinical studies using combinations of drugs that target IGF1R and mTOR axis.
2. Marc Ladanyi found increased expression of IGF2 in ASPS tumors (see Vistica abstract)
3. Vistica found that adding IGF in his in vitro model of ASPS caused the tumor cells to grow.

Our daughter is still on the ARQ197 trial, but we do try to keep up with pipeline agents, and this looked promising and is different from antiangiogenesis and met inhibitors (not that these agents aren't effective - this is just a different category of drug). It is also unusual (like ARQ197) in that they accept children into the study.

[Fictional]

p.s. This is the link to David Vistica's ASPS in vitro paper:
http://www.aacrmeetingabstracts.org/cgi ... 2004/1/265

[Olga]

As per our oncologist, there is a documented and ongoing partial response to R1507 in an ASPS patient that is on a clinical trial somewhere so now this trial additionally enrolls a few ASPS North Am. wide. The duration and size of the response is unknown to me at this point, I hope that may be the person on a trial could see this post and comment?

[Olga]

Some relevant information from the ASCO 2007 meeting re. this drug:

A phase I study of q3W R1507, a human monoclonal antibody IGF-1R antagonist in patients with advanced cancer.
Sub-category:

Receptor-Targeted Antibodies/Ligands
Category:

Developmental Therapeutics: Molecular Therapeutics
Meeting:

2007 ASCO Annual Meeting

Printer Friendly
E-Mail Article
Abstract No:

3590
Citation:

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 3590
Author(s):

J. Rodon, A. Patnaik, M. Stein, A. Tolcher, C. Ng, C. Dias, M. Kurman, G. Greig, R. Kurzrock, E. Rubin
Abstract:

Background: Insulin-like growth factor receptor (IGF-1R) is a tyrosine kinase cell surface receptor overexpressed in cancer cells which mediates the mitogenic and anti-apoptotic actions of IGF, playing a key role in malignant transformation. The safety and pharmacokinetics of 3-weekly administration of R1507, a human monoclonal antibody selective for IGF-1R, were explored in this phase I dose escalation study in patients with advanced solid tumors or lymphomas. Materials and Methods: Multiple ascending doses of R1507 were administered as a 1 hour infusion every 3 weeks until the development of dose-limiting toxicity (DLT) or progressive disease. Inclusion criteria: ECOG PS 0-1, adequate hematologic, hepatic, and renal function, CD4 count >200/µl. Exclusion criteria: infection, immunosuppressive agents, diabetes mellitus, uncontrolled systemic disease, NYHA III/IV CHF. DLT defined as > grade 2 hypersensitivity reaction; > grade 3 non-hematologic toxicity; > grade 2 cardiac toxicity; > grade 3 hematologic toxicity = 7 days, or dose delay > 1 week due to toxicity. Blood samples were collected following 1st dose for non compartmental PK analysis and for future analysis of IGF-1R levels. Results: 21 patients (pts) (M:F 14:7) were enrolled in 1 of 4 dose levels (dose range 1-16 mg/kg). Mean pt age 57 yrs (range: 30-81), mean prior treatments 4.6 (range: 1-9). Mean treatment cycles 2.6 (range: 1- 6). Six pts remain on study. Adverse events (AE) included infection (6 pts), fatigue (4); rash, fever, arthralgia, cough, diarrhoea, abdominal and back pain (3 each). No DLT or serious AEs attributed to study drug were reported. Activity: 10 pts showed stable disease (median 33 days). PK: Clearance (CL) decreased from 812 mL/Day (Coefficient of Variation [CV] =19.9%) in the 1 mg/kg group to 418 mL/Day (CV=46.7%) in the 16 mg/kg group; Volume of distribution was in the range of 4.4 - 5.4 L (CV=10.9-34.8%). T1/2 increased from 4 to 9 days. Conclusions: Treatment with R1507 is tolerable at the dose of 16mg/kg q3W. Treatment-related toxicities are mild and clinically manageable. Decrease in CL across doses levels suggests a saturable elimination pathway. T1/2 value of ~8 days supports a weekly dosing for future trials.

[Fictional]

Oops. Sorry if I posted twice somewhere. I meant to save it and it seemed to disappear. We raised a lot of money for 'K''s fund so we decided to pay to review the ASCO Cancer meetings which discuss a lot of new agents and sarcoma. It is a very complicated field.

I will try to attach a screen shot of an ASPS case they presented that responded to R1507. The nice thing about R1507 is that it seems well tolerated. This picture is not the best, but it does seem to show something smaller in the lungs. R1507 is very well tolerated as far as these agents go. And kind of stupid - I said that 'K''s tissue was not IGFR positive, but that' not true...50% IGFR-positive with 2+ staining.

Check out Lucio's post for more details. Don't know if the ASPS case that he was told about was the same one as in this picture.

R1507 is given once a week IV. Apparently there is no dose limiting response. Some of the pictures of other sarcomas is dramatic. It has been one of the fastest accruing sarcoma studies - perhaps word got out about its success and low side effects. I know I read about girl who was on R1507 - and she was able to continue cheerleading while on it. Not ASPS, though - another sarcoma. The fatigue is not as bad as of the other drugs. I also checked IMC-A12 as it is another IGF1R drug that is available in Seattle - the preliminary evidence from this one is not as good as for R1507. There is also some interest in combining these with e.g. mTORs.

Picture 44.png (112.51 KiB) Viewed 12208 times

[Olga]

R1507 is avail. on a clinical trial in Vancouver...

[Fictional]

I think it's available lots of places. It's a really big Phase II. 63 sites:
http://clinicaltrials.gov/ct2/show/stud ... ocs=Y#locn

Keep going back and forth about whether to do an mTOR first or R1507. I don't know if they've opened it yet in Seattle. What I like about the R1507 results is that they are seen within 2-3 months. I get the feeling the mTORs are a little slower...

[Olga]

Roche has informed Genmab that it will discontinue development of RG1507
http://www.pharmalive.com/News/Index.cf ... eid=671289
Copenhagen, Denmark; December 4, 2009 -


Genmab A/S (OMX: GEN) announced today that Roche
has informed Genmab that it will discontinue
development of RG1507, a monoclonal antibody
directed against the insulin-like growth factor-1
receptor (IGF-1R). The decision was due to the
available clinical data, the large number of
molecules targeting the same pathway that are
presently in development and the prioritization of
the Roche portfolio. The decision was not as a
result of safety concerns.

RG1507 is a fully human antibody created by Genmab
under its collaboration with Roche. RG1507 was in
Phase II development for multiple indications
including sarcoma and non small cell lung cancer.

[Bonni Hess]

Thank you for posting this important information Olga. I Hope that this decision will not result in 'K' being taken off of the R1507 Clinical Trial which has seemed to provided encouraging disease stabilization for her. Do you know what the implication is for patients who are currently on an R1507 Trial?
With special caring thoughts and continued Hope,
Bonni

[Fictional]

Thanks gals. Didn't dare to breathe about this - called SARC, thank God - they have a guarantee in writing from Roche that any patients currently on trial can continue to receive the drug.

SARC was shocked initially because R1507 has had some of the most dramatic effects on sarcoma - especially pediatric Ewing sarcoma. At the ASCO trials its one of the most dramatic presentations I'd ever seen. The problem is that Genentech has a rival drug IGFR1 Ab and Genentech is merging with Roche (an aside - this is still crazy to drop R1507- as not all inhibitors are alike...take a look at VEGF inhibitors, and Imclone IGFR1 Ab is certainly not as good as R1507). Unfortunately sarcoma is not a blockbuster cancer category because it is so rare.

We would like to be on this drug as long as possible. Even beyond keeping her cancer stable - this drug's mechanism may kill dividing cells - so may have more effect in a slow dividing cancer if taken over a long time. Like ARQ, there is some suggestion that it may help kill new metastases / developing new tumors and we would like to kill dividing stem cells if we can.

BTW if you have contacts with Ewing Sarcoma, Daniela Gula (SARC) told me this morning that Roche has also guaranteed that it may complete the accrual for Ewing sarcoma patients.