Big antibody news

The “third generation” humanized anti-GD2 antibody with protein fusion of IL2 to the antibody has completed Phase I and II clinical trials for melanoma and neuroblastoma, and is now ready for use in Phase III clinical trials. The license for hu14.18-IL2 was just acquired by a small biotech in Vienna called Apeiron. The license was acquired from Merck.

Apeiron’s press release:

Apeiron Licenses Phase II/III Anticancer Ab-IL2 Fusion Protein from Merck KGaA

Long-term follow up of children with and without ch14.18/CHO in German trials NB90 and NB97

It has been a very long wait to finally see this graph. The Germans reported on this at ANR 2008 in Japan, and again at ANR 2010 in Stockholm.  See Graph A in Figure 2. “Follow-up analysis of the patient cohort indicated that immunotherapy with ch14.18 [no cytokines] may prevent late relapses.” Remember this group reported in 2004 “analysis failed to demonstrate an advantage of antibody treatment” –

http://jco.ascopubs.org/content/22/17/3549.long

.

The statement about late relapses is a little puzzling to me. Graph A shows that “events” (which are usually relapses) occurred up until 10 years in both the ch14.18 and maintenance groups. Only the “no consolidation” group had later events.

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The authors concluded:”Today, the most effective way of antibody based maintenance therapy seems to be a combination immunotherapy with MAB ch14.18, cytokines, and retinoic acid. But these results need confirmation by at least another randomized trial. Further, metronomic low dose oral chemotherapy consolidation was found as effective as MAB ch14.18 consolidation in this retrospective analysis and, therefore, also warrants further evaluation. Prospective clinical trials must demonstrate if the concept of low dose metronomic chemotherapy is feasible and effective after ASCT and in combination with immunotherapy.”

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Since the early results did not show a benefit of ch14.18 without cytokines, and yet the COG trial showed 20% advantage in early results, it could be argued that there might be a big difference in survival between oral metronomic chemotherapy and ch14.18 with cytokines.

http://www.biomedcentral.com/content/pdf/1471-2407-11-21.pdf

Germans report on outcomes of relapsed NB patients who received three different regimens

Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials.

Simon, T., Berthold, F., Borkhardt, A., Kremens, B., De Carolis, B. and Hero, B. (2011), Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials. Pediatric Blood & Cancer, 56: 578–583. doi: 10.1002/pbc.22693

This is an important publication and was presented at ANR 2010. Few groups have tackled relapsed NB in any systematic way. Wendy London’s abstract presented at ASCO 2010 and ANR 2010 on survival after relapse suggests that some relapsed NB children are salvageable, and the Germans and Swedes are advancing understanding in treating relapse. This same approach looking at more aggressive measures for relapsed leukemia kids is how relapse protocols were developed to treat relapsed leukemias.

Drs John Maris and Yael Mosse awarded patent for ALK mutation link to diagnosis, prognosis, and treatment of neuroblastoma

Summary of patent:

CHK1 suspected to be a promising target in NB — inhibitors are being tested in adults

‎”CHK1 mRNA expression was higher in MYC–Neuroblastoma-related (MYCN)–amplified (P < 0.0001) and high-risk (P = 0.03) tumors.”

RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in n

www.pnas.org

Edited by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved December 17, 2010 (received for review August 23, 2010)

Protein May Be Key to New Treatment in a Childhood Cancer — PHILADELPHIA, Feb. 7, 2011 /PRNewswire-

Rare news

A disease that afflicts only 350 children per year in the US (in the high-risk form) does not make headlines very often. But after the September 30, 2010 publication of the New England Journal of Medicine article revealing the results of the phase III chimeric antibody trial (ch14.18 given with two cytokines GM-CSF and IL2), neuroblastoma was all over the news including prime time national news. Over 200 news stories appeared within the next 2 days and over 3000 blogs reported on the story. Click on image below for a nice example of one of the medical blogs:

From Science Life blog at University of Chicago

The news was actually first released March 19, 2009 after an early review of the study. The study was amended so that the randomization was stopped and all eligible children could  receive the antibody.

This is quite a dramatic story on many levels.

An absolute must read is an excellent article giving more background on the story in the NCI Cancer Bulletin. The article details the incredible perseverance required of Dr Alice Yu, Dr Paul Sondel, Dr Malcolm Smith, and the entire COG team to bring this antibody to children with neuroblastoma. The research on this antibody began in 1985, and yet it took 25 years to get solid proof that the antibody improves survival. Why did it take so long?

Antibody and drug development are not the same

Antibodies are first isolated from mice that are “challenged” with a tumor and produce antibodies against that tumor. The production is shown in the illustration below from a wikipedia article which describes the process:

This particular antibody targets GD2 which is a glycolipid (sugar-fat) antigen on the surface of NB cells. This antigen is also present on other cancers, including melanoma. GD2 is also expressed on some normal nerve cells, which is why the treatment causes pain. “First generation” antibodies are entirely mouse products (termed “murine”) and is why a normal immune system reacts quickly to produce anti-mouse human antibodies (HAMA) which effectively neutralize the action of the mouse antibody. Examples of first generation anti-GD2 antibodies are Memorial Sloan-Kettering’s 3F8 antibody (research also began in 1985[1]) and 14G1,14G2b, and 14G2a antibodies.[2]  The ch14.18 chimeric antibody is a “second generation” anti-GD2 antibody, since it has been engineered to be 75% human and 25% mouse in makeup, and why it is labeled chimeric (a “mix” of human and mouse). This greatly reduced the incidence of forming antibodies against the ch14.18. Two “third generation” antibodies that are fully humanized have been developed to date  and have been tested in clinical trials:

• St Jude’s hu14.18K322A, in a phase 1 study now for neuroblastoma and melanoma, and given without cytokines
• hu14.18-IL2, a fusion protein where the cytokine IL2 is attached to the antibody (in phase 2 study now for melanoma)

The hu14.18-IL2 antibody has already shown significant efficacy in a phase II study for relapsed and refractory neuroblastoma with results just published in October 4, 2010 issue of the Journal of Clinical Oncology.[3]

Plans are underway now for both ch14.18 and hu14.18-IL2 to be used in further clinical trials in combination with other promising agents for relapsed/refractory neuroblastoma and these trials will begin accruing at COG institutions in 2011.

More to the story

Ironically, this pivotal phase III ch14.18 trial that showed such a dramatic improvement to survival had some difficulty accruing. It is interesting to note that the other recent phase III studies all accrued patients at a relatively even pace (~90-100 patients per year) with the exception of this ch14.18 antibody study:

• CCG-3891 (1991 – 1996) double randomization of transplant and cis-retinoic acid accrued 539 over 6 years or ~ 90 per year [4]
• COG-A3973 (2001 – 2006) randomization for purge vs no purge of stem cells for stem cell transplant accrued 489 over 5 years or ~ 98 per year [5]
• COG-ANBL0032 (2001 – 2009) randomization of ch14.18 vs no ch14.18 accrued 226 over 7.5 years or ~ 30 per year [6]
• COG-ANBL0532 (2007 – 2012) randomization of single vs tandem transplant is accruing on schedule (should be complete by fall 2012) at 495 over 5 years or ~ 99 per year [7]

The striking fact is that if the early analysis had not revealed a significant difference in outcome, accruing at this rate this trial might have been ongoing until 2014.

Medical ethics, trial design, and real children

With success also comes inevitable heart ache. Hindsight can be a bitter pill to swallow. It is impossible to forget the children who did not receive the antibody and had increased chance of relapse as a result. By the time 2 years elapsed from randomization, 38/113 children had relapsed after receiving the antibody,  but 61 children had relapsed after receiving no antibody, an excess incidence of relapse in 23 children. Was it really necessary to randomize the antibody? If it was a promising treatment why was it not just given to everyone?

There are no easy answers to this fair and difficult question. While there were high hopes the ch14.18 antibody given with two cytokines would help, no one really knew if it would make a difference in survival. After all, in 2004 the German study group (GPOH) had published their retrospective findings that the ch14.18/CHO antibody (made with hamsters instead of mice, and given without cytokines) made no difference in survival when groups were compared from GPOH NB90 and NB97 protocols.[8]

A perfect example of this very quandary was played out with neuroblastoma not long ago. A method was devised in the early 1990s to purge stem cells of neuroblastoma with monoclonal antibodies (of all things) and magnetic beads. The purged stem cells could then be frozen and returned to children after high-dose (myeloablative) chemotherapy. This idea made so much sense: why not clean up the stem cells first and remove the risk of re-infusing the child with NB cells?

Fast forward to the negative results of a very costly and lengthy phase III study — purging had made no difference at all in the survival of high-risk NB children. These results were presented at the 2007 ASCO meeting, but are still not published to date. [9]

So what are the implications? The purging costs upwards of $30,000 per child. It also wastes 50% or more of the stem cells in the process. Knowing that this expensive, wasteful  process is not needed is a very important finding. A similar finding could have been in store for ch14.18 with cytokines. Randomizing is not necessary when a dramatic and consistent response results from a treatment. Not every child responded to ch14.18 treatment in earlier studies, so efficacy had to be proven before it could become a standard treatment. After all, 5 months of ch14.18 treatment with cytokines is a very expensive and complex ordeal, and children are required to spend up to 7 additional weeks in the hospital for this intensive treatment.

In the midst of the celebration over this genuine breakthrough, it is nevertheless heartbreaking to realize that a total of 99 children out of the 226 (both groups) had relapsed by two years — or 44%. It is poignant to note that each of the researchers interviewed about this remarkable study also made the comment “We must do better.” There is an impressive array of researchers and clinicians who have dedicated their entire careers to pushing that sad high-risk neuroblastoma survival curve upward. They see the faces of the children who have been lost along the way in those curves too.

Costly development and production

Developing an antibody (a biopharmaceutical) is far more complex that developing a drug. Cost of production and additional regulatory requirements make this an expensive endeavor. For example, $8 million of 2009 stimulus funds were awarded December 2009 to SAIC-Frederick (NCI research partner) to produce a two year supply of ch14.18:

NCI, through the BDP [Biopharmaceutical Development Program], is to deliver sufficient number of vials of finished product to treat all neuroblastoma patients for whom antibody Ch14.18 has become the clinical standard of care. This 2-year interval for NCI production can be used as a transition to licensing and commercial production. In addition, for the Cancer Immunotherapy Network, the NCI, through the BDP, will develop and supply vials of agents of great interest of the extramural community for further clinical investigation.

Transitioning is currently underway for United Therapeutics to begin producing ch14.18, and complete the FDA registration process. Keeping an eye on further use in melanoma is of interest since that will potentially make ch14.18 a more profitable product for United Therapeutics.[10]

Implications for Europe

At ANR (Advances in Neuroblastoma Research) in 2008 and 2010 and at SIOP 2009 the German group (GPOH) reported that after longer follow-up, the ch14.18/CHO treatment might prevent late relapses. The GPOH is planning to reintroduce ch14.18/CHO treatment. The large SIOP trial SIOP-EUROPE-HR-NBL-1 opened in 2002 and had planned to randomize ch14.18 but since the results of the COG study, the SIOP study was amended to give all eligible children ch14.18 with or without subcutaneous IL2. There is such a great body of evidence showing that GM-CSF is an essential part of this treatment, hopefully the regulatory hurdles will be quickly resolved and children in Europe will soon have the opportunity to get this better treatment regimen. See John Roger’s ANR report for more on this very important subject.

References

1. Biochem Biophys Res Commun. 1985 Feb 28;127(1):1-7. Ganglioside GD2 specificity of monoclonal antibodies to human neuroblastoma cell.

2. Cancer Research 49, 2857-2861, June 1, 1989. Functional Properties and Effect on Growth Suppression of Human Neuroblastoma Tumors by Isotype Switch Variants of Monoclonal Antiganglioside GD2 Antibody 14.18

3. J Clin Oncol. 2010 Oct 4. Antitumor Activity of Hu14.18-IL2 in Patients With Relapsed/Refractory Neuroblastoma: A Children’s Oncology Group (COG) Phase II Study

4. J Clin Oncol. 2009 Mar 1;27(7):1007-13. Long-Term Results for Children With High-Risk Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy Followed by 13-cis-Retinoic Acid: A Children’s Oncology Group Study

5.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9505 Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG A3973) study

6. N Engl J Med. 2010 Sep 30;363(14):1324-34. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.

7. Correspondence with investigators

8. J Clin Oncol. 2004 Sep 1;22(17):3549-57. Consolidation treatment with chimeric anti-GD2-antibody ch14.18 in children older than 1 year with metastatic neuroblastoma.

9.  Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 9505 Response and toxicity to a dose-intensive multi-agent chemotherapy induction regimen for high risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG A3973) study

10.  Clinical Cancer Research August 1997 3; 1277 Phase IB trial of chimeric antidisialoganglioside antibody plus interleukin 2 for melanoma patients.

Pilot study: 131I-MIBG radiotherapy with chemotherapy after induction for newly diagnosed

Dr Greg Yanik (University of Michigan) presented preliminary results of the NANT (New Approaches to Neuroblastoma Therapy) NANT-2001-02 phase 2 MIBG + CEM (131I-MIBG radiotherapy with carboplatin, etoposide, and melphalan) stem cell transplant trial on June 23rd 2010 at the Advances in Neuroblastoma Research meeting in Stockholm, Sweden in the “Novel clinical strategies” session. The data are still under review and will be presented at the COG meeting next month. The trial has been completed but the NIH clinical trials listing has not yet been updated to reflect this.[1]

The results of 12 relapsed and refractory children treated in the phase I MIBG+CEM trial was published in 2002.[2]

The encouraging results in the phase II study with 50 refractory children who did not completely respond to induction provide promising expectations for a new pilot trial COG-ANBL09P1 using this concept for frontline therapy for newly diagnosed. The principal investigator is Dr Brian Weiss (Cincinnati Children’s) and the trial will soon begin, accruing 49 patients up to 30 years old in select locations.

Upon completing this protocol, children will also be eligible for the new phase III antibody study using ch14.18 + GM-CSF + IL2 COG-ANBL0931. This trial opened in January 2010 and will accrue 105 (currently open in 29 locations) to further establish safety and efficacy of the antibody ch14.18 given with cytokines GM-CSF and IL2 to obtain FDA approval. This trial is open to all ages.

Is this the first time MIBG will be used in frontline therapy for newly diagnosed (as opposed to just for those refractory at the end of induction)? In 2008 researchers in the Netherlands reported the use of MIBG as initial therapy before chemotherapy and surgery for 44 newly diagnosed high-risk children.

From the abstract:

The protocol dictated at least two cycles of (131)I-MIBG with a fixed dose of 7.4 and 3.7 GBq, respectively, followed by surgery, if feasible, or followed by neoadjuvant chemotherapy and surgery. This was followed by consolidation with four courses of chemotherapy myeloablative chemotherapy and autologous stem-cell transplantation (ASCT). Consolidation therapy with 13-cis-retinoic acid was given for 6 months.

Of 44 consecutive patients, 41 were evaluable after two courses of (131)I-MIBG. The objective response rate at this point was 66%. In 24 patients, (131)I-MIBG was continued as pre-operative induction treatment. Seventeen patients required additional chemotherapy before surgery. After pre-operative therapy and surgery, the overall response rate was 73%.[3]

References

1. OR58 Phase II trial of MIBG with intensive chemotherapy and Autologous Stem Cell Transplant (ASCT) for high risk neuroblastoma. A New Approaches to Neuroblastoma Therapy (NANT) Study (p. 123 ANR Programme Abstract Book, June 2010)

2. J Clin Oncol. 2002 Apr 15;20(8):2142-9. Pilot study of iodine-131-metaiodobenzylguanidine in combination with myeloablative chemotherapy and autologous stem-cell support for the treatment of neuroblastoma. PMID: 11956276

3. Eur J Cancer. 2008 Mar;44(4):551-6. Epub 2008 Feb 11. Iodine-131-metaiodobenzylguanidine as initial induction therapy in stage 4 neuroblastoma patients over 1 year of age. PMID: 18267358

Dr Peter Zage from MD Anderson in Houston TX gave a presentation at the Children’s Neuroblastoma Cancer Foundation (CNCF) conference Saturday July 10, 2010 on the 3F8 randomized trial:

A Study of MAb-3F8 Plus Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Versus 13-cis-Retinoic Acid (RA) Plus GM-CSF in Primary Refractory Neuroblastoma Patients (NCT00969722)

This trial is funded by United Therapeutics, who recently retained rights to 3F8. This trial is currently open in 15 locations and began accruing in 2009, with a planned accrual of 40 children 18 months to 13 years old. United Therapeutics has also entered into an agreement with Memorial Sloan-Kettering Cancer Center (MSKCC) to exclusively license certain rights to the  antibody 8H9, used for brain relapse of certain tumors, including neuroblastoma.

This phase II randomized trial is a “registration trial” with the goal of gaining FDA approval for 3F8. The objective is to compare response rates in children with primary refractory disease to either 3F8 + GM-CSF or cis-retinoic acid (Accutane) + GM-CSF. Children who do not respond after two cycles may cross over to the other arm for the next two cycles. The children who have primary refractory disease–defined in this case as bone marrow or bone disease after induction or transplant, but no soft tissue disease– represent roughly 10% of all NB high-risk cases, or about 30 per year in the US, according to Dr Zage.  Children are not eligible if they have soft tissue disease, brain metastases, and they cannot have radiation during this trial.

A phase III (non-randomized) registration trial COG-ANBL0931 also opened in January 2010 and will accrue 105 patients: “Monoclonal Antibody Ch14.18, Sargramostim, Aldesleukin, and Isotretinoin After Autologous Stem Cell Transplant in Treating Patients With Neuroblastoma.”  The purpose of this trial is to gain FDA approval for the ch14.18 antibody.  According to the NIH clinical trials listing it is currently open in 29 locations. This trial also allows residual disease (primary refractory after stem cell transplant) by MIBG scan, CT scan, MRI, bone marrow aspiration, or biopsy.

The landmark phase III study COG-ANBL0032 that revealed efficacy for ch14.18 with IL2 and GM-CSF upon early analysis is also still open in 155 locations, with randomization ceased so all enrolled will receive ch14.18 (with GM-CSF and IL-2). [1]  The trial will accrue a total of 423. This trial also allows primary refractory disease described by the protocol.

Dr Zage gave a brief history of the development, production, and use of monoclonal antibodies in neuroblastoma. [2]

This is the first time 3F8 antibody has been available at an institution other than Memorial-Sloan Kettering in New York or Queen Mary Hospital in Hong Kong.

References

1. J Clin Oncol 27:15s, 2009 (suppl; abstr 10067z)

2. Cancer Biol Ther. 2009 May;8(10):874-82. Epub 2009 May 9. Review. [fulltext]

MIBG non-avid at diagnosis = better outcome?

POC39 (p. 211) Neuroblastomas with non-avid I-123 MIBG scan and negative urinary catecholamine secretion: A single institute’s experience

PL30 (p. 102) Analysis of MIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma. A Children’s Oncology Group (A3973) report

Dui Yen Soh, Sylvain Baruchel, and Meredith Irwin at Sick Kids in Toronto reviewed 148 children diagnosed between 1999 and 2009 (all stages and risk groups). They confirmed the interesting observation that non-avid MIBG and negative urine catecholamines at diagnosis are associated with low stage and favorable outcome. Of the MIBG non-avid children, 5 were low risk, 3 were intermediate risk, and 3 were high risk. These numbers are too small to confirm better outcome for MIBG non-avid (at diagnosis) high-risk, but Greg Yanik (University of Michigan) mentioned an interesting observation of better survival for those high-risk children who are MIBG non-avid at diagnosis (of n= 280 enrolled in COG-A3973, 29 were MIBG negative at diagnosis) in his presentation on a new scoring method to stratify patients at the end of induction. He presented at ASCO 2010 Chicago, ANR 2010 Stockholm, and will present again next week at the CNCF Parent Conference in Chicago. More on Dr Yanik’s presentation to come.[1]

Any ideas why MIBG non-avid survival might be better? No answers proposed yet.

Tandem transplant in Korea

POC40 (p. 211) Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients with high-risk Neuroblastoma: a preliminary report of NB 2004 study at Samsung Medical Center (Republic of Korea)

Ki Woong Sung and group reported at ANR results of 47 children diagnosed 2004 to 2008 and enrolled on NB 2004.  Of the 44 patients that went through tandem transplant, 36 (82%) remain event-free after median follow-up of 3 years (14-72 months) with probability of 5 year overall and event-free survival determined to be 68% ± 20%  and 67% ±  16%, with no treatment-related deaths.  Another report from the same center in 2007 gave results of 52 children diagnosed from 1997 to 2005 (44 had second SCT with TBI).  That study had 15% treatment-related deaths, 33 (75%) were event-free with median follow-up of 53 months (19-117 mo) from diagnosis.[2]  A retrospective study of 141 patients enrolled 2000 to 2005 from the Korean Society of Pediatric Hematology-Oncology (KSPHO) published May 2010 also showed improved 5-year event-free survival in the tandem group over the single transplant group (51 ±12% vs. 31 ±12%, P=0.030).[3]

Korean single and tandem retrospective study 1997 to 2005

These studies show strikingly comparable results to a larger COG pilot (97 children diagnosed 1994 to 2002) reported in 2006, which was the rationale for the current frontline single-versus-tandem trial in the COG.[4]

Germans report no difference in outcome using cis-retinoic acid (Accutane) or ch14.18/CHO antibody

POC37 (p. 210) Comparison of anti-GD2-antibody ch14.18 and 13-cis-retinoic acid as consolidation therapy for high-risk neuroblastoma. Results of the German NB97 trial

Thorsten Simon and group from GPOH (German pediatric oncology study group) reported retrospectively on two similar—but not randomized groups—showing that the outcome was not statistically different with almost 8 years of median follow-up for 74 children who received only ch14.18 antibody (1997-2002) and 75 children who received only cis-retinoic acid (2002-2004). The 3-year event-free survival from diagnosis was 53% ± 6% and 51% ± 6% (p=.209) respectively. While this result is interesting with regard to single-agent efficacy, it is very important to note that none of the children received both antibodies and cis-retinoic acid, nor were the children given cytokines (IL2 or GM-CSF) with the antibody as in the current COG trial. The GPOH previously reported no advantage to ch14.18 (no cytokines) over oral maintenance chemotherapy.[5]  But at ANR 2008 (Japan) the GPOH group reported no late relapses in the ch14.18 group. At this 2010 ANR they also said they have now seen a difference in the retrospective study after 10 years with statistically significant improved survival for the ch14.18 group. During the Special Clinical Session at ANR on Tuesday Dr Thorsten Simon said the GPOH will be revisiting the question of ch14.18/CHO given the remarkable survival advantage shown in the COG study report from Mar 2009.[6]  They are now considering using subcutaneous administration of IL2 to reduce toxicity (as is SIOP in the UK and the rest of Europe), and exploring the use of other agents such as IL15 or lenalidomide with the antibody.

References

1. J Clin Oncol 28:15s, 2010 (suppl; abstr 9516)
2. Bone Marrow Transplant. 2007 Jul;40(1):37-45. Epub 2007 Apr 30. PMID 17468771
3. J Korean Med Sci. 2010 May;25(5):691-7. Epub 2010 Apr 21. PMID 20436703 [full text]
4. J Clin Oncol. 2006 Jun 20;24(18):2891-6. PMID: 16782928 [full text]
5. J Clin Oncol. 2004 Sep 1;22(17):3549-57. PMID: 15337804
6. J Clin Oncol 27:15s, 2009 (suppl; abstr 10067z)