Preliminary results suggest that it may be an effective agent for sarcoma. AP23573 exhibits single-agent activity in pts with advanced sarcomas in a phase II study. A clinical study with AP23573-07-302 (Ariad) is ongoing.

JS. P. Chawla, A. W. Tolcher, A. P. Staddon, S. Schuetze, G. Z. D’Amato, J. Y. Blay, J. Loewy, R. Kan, G. D. Demetri Survival results with AP23573, a novel mTOR inhibitor, in patients (pts) with advanced soft tissue or bone sarcomas: Update of phase II trial.
Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 10076

Rizzieri, David A., Feldman, Eric, DiPersio, John F., Gabrail, Nashat, Stock, Wendy, Strair, Roger, Rivera, Victor M., Albitar, Maher, Bedrosian, Camille L., Giles, Francis J.
A Phase 2 Clinical Trial of Deforolimus (AP23573, MK-8669), a Novel Mammalian Target of Rapamycin Inhibitor, in Patients with Relapsed or Refractory Hematologic Malignancies
Clin Cancer Res 2008 14: 2756-2762

Both Torisel and Avastin are effective for renal cell carcinoma. Torisel is FDA approved as a single agent. Avastin is also an effective treatment for renal cell carcinoma.

Several studies indicate that Avastin is effective for renal cell carcinoma. A randomized, double-blind, Phase II trial was conducted comparing placebo with bevacizumab at doses of 3 and 10 mg per kilogram of body weight, given every two weeks in 166 patients with renal cancer, with significant positive results for Avastin. According to updated results from a phase II clinical trial presented at the 23rd annual Chemotherapy Foundation Symposium, treatment with the combination of Tarceva® (erlotinib) and Avastin® (bevacizumab) resulted in good survival among patients with metastatic renal cell carcinoma. Current NCCN guidelines recommend Avastin as an option for crossover therapy of renal cell carcinoma after first line therapy with IL2, sorafenib or sunitinib.

The combination of the two drugs, however, is not proven becauseit does not have scientific evidence the permits conclusions ot its effect on health outcomes and the above noted trials are ongoing.

Coppin C, Porzsolt F, Awa A, et al. Immunotherapy for advanced renal cell cancer. Cochrane Database Systematic Rev. 2004;3:CD001425.

Hainsworth J, Spigel D, Greco A. Combination Therapy with Bevacizumab and Erlotinib for Patients with Metastatic Clear Cell Renal Carcinoma. Proceedings from the 23rd annual Chemotherapy Foundation Symposium. New York. 2005; Abstract #22.

Aimery de Gramonta, Eric Van Cutsemb, Investigating the Potential of Bevacizumab in Other Indications: Metastatic Renal Cell, Non-Small Cell Lung, Pancreatic and Breast Cancer, Oncology Suppl. 3, 2005

SWOG 0012 was a precursor for an ongoing adjuvant trial (SWOG 0221) that is looking at a novel approach to the administration of chemotherapy based on previous studies showing that metronomic dosing can overcome chemotherapy resistance in a variety of model systems.

SWOG 0012 compared standard chemotherapy to the metronomic approach in the neoadjuvant setting.13 The primary endpoint was pCR. A total of 372 patients with LABC or infl ammatory breast cancer (IBC) were enrolled in the study, with 265 evaluable for primary outcome. Metronomic chemotherapy consisted of doxorubicin 24 mg/m2/week and oral cyclophosphamide 60 mg/m2/day for 15 weeks, with weekly granulocyte colony-stimulating factor (G-CSF) support. In previous trials, patients who did not receive growth factors had an increase in dermatitis as well as hematologic toxicity, which was ameliorated with G-CSF support. The control arm received every-3-week doxorubicin/cyclophosphamide at standard doses for 5 doses (as opposed to the standard 4). Both treatment groups then received standard weekly paclitaxel for 12 weeks. Approximately 30% of the patients had IBC, so this was a very locally advanced disease group. The toxicity between the arms was similar to that seen in prior studies (13% grade 3/4 hand-foot syndrome [HFS] associated with metronomic dosing vs. 0 with standard treatment), but neutropenia was markedly reduced because of the G-CSF (16% with metronomic dosing vs. 47% with standard treatment). There was very minimal difference in reports of febrile neutropenia.

The response results are quite striking. There was a statistically significant difference in pCR rate at the primary site of 19% in the standard arm compared to 31% in the metronomic arm. This is one of the highest pCR rates reported in IBC. Considering patients who had both pCR and node negativity, the difference is also striking: 15% in the standard arm compared to 26% with metronomic-dose chemotherapy. The metronomic regimen is clearly quite tolerable, HFS being the major toxicity, with fewer hematologic side effects and what appears to be improved efficacy compared to standard dosing. This study demonstrates that occasionally data from preclinical models can inform the clinical setting with very positive results. The very encouraging clinical results support enrollment to SWOG 0221, an ongoing adjuvant trial comparing dose-dense chemotherapy to the metronomic approach. This is a phase III Trial of Continuous Schedule AC + G Vs. Q 2 Week Schedule AC, Followed by Paclitaxel Given Either Every 2 Weeks or Weekly for 12 Weeks as Post-Operative Adjuvant Therapy in Node-Positive or High -Risk Node Negative Breast Cance The arms are:
Arm 1: Patients receive Adriamycin and Cytoxan IV every two weeks for 12 weeks (6 cycles). This is followed by Paclitaxel every two weeks for 12 weeks. On the day after each chemotherapy, a dose of sub-q Pegfilgrastim is given.

Arm 2: Patients receive Adriamycin weekly for 15 weeks. They take oral Cytoxan daily for 15 weeks. During this period, patients will give themselves a daily sub-q injection of Filgrastim, except on days they receive Adriamycin. This is followed by Paclitaxel every two weeks for 12 weeks. On the day after each Paclitaxel dose, patients receive a sub-q injection of Pegfilgrastim.

Arm 3: Patients receive Adriamycin and Cytoxan (AC) IV every two weeks for 12 weeks (6 cycles). On the day after each dose of AC, a dose of sub-q Pegfilgrastim is given. This is followed by Paclitaxel given weekly for 12 weeks.

Arm 4: Patients receive Adriamycin weekly for 15 weeks. They take oral Cytoxan daily for 15 weeks. During this period, patients will give themselves a daily sub-q injection of Filgrastim, except on days they receive Adriamycin. This is followed by Paclitaxel given weekly for 12 weeks.

Arm one is currenlty the only standard of care arm.

Obviously, this is an experimental approach and the treatment offfered on this trial, unless it is on arm 1, is considered experimental under the plan’s defintion. The assigned Arm is not known or we have not been advised. IF ti turns out to be Arm 1, the case can be re-reviewed or appealed.

Ellis GK, Livingston RB, Gralow JR, et al. Dose-dense anthracycline-based chemotherapy for node-positive breast cancer. J Clin Oncol 2002; 20:3637-43. Ellis GK, Barlow WE, Russell CA, et al. SWOG 0012, a randomized phase III comparison of standard doxorubicin (A) and cyclophosphamide (C) followed by weekly paclitaxel (T) versus weekly doxorubicin and daily oral cyclophosphamide plus G-CSF (G) followed by weekly paclitaxel as neoadjuvant therapy for infl ammatory and locally advanced breast cancer. J Clin Oncol 2006; 24(suppl):933s (abstract LBA537). nccn.org, breast cancer

Unfortunately, clinical use is in its infancy. Until simpler and more rapid tests become commercially available, phenotyping may remain largely a research tool, or one with applicability limited to special populations likely to have significantly abnormal activity, particularly those patients who are suspected to have liver disease, declining hepatic function, or who may be receiving inducers or inhibitors of CYP3A4.

E. D. Kharasch, K. E. Thummel, and P. B. Watkins
CYP3A Probes Can Quantitatively Predict the In Vivo Kinetics of Other CYP3A Substrates and Can Accurately Assess CYP3A Induction and Inhibition
Mol. Interv., June 1, 2005; 5(3): 151 – 153.

Noboru Yamamoto, Tomohide Tamura, Haruyasu Murakami, Tatsu Shimoyama, Hiroshi Nokihara, Yutaka Ueda, Ikuo Sekine, Hideo Kunitoh, Yuichiro Ohe, Tetsuro Kodama, Mikiko Shimizu, Kazuto Randomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous CortisolRandomized Pharmacokinetic and Pharmacodynamic Study of Docetaxel: Dosing Based on Body-Surface Area Compared With Individualized Dosing Based on Cytochrome P450 Activity Estimated Using a Urinary Metabolite of Exogenous Cortisol JCO 2005 23: 1061-1069

Capecitabine (Xeloda) is a drug that damages the DNA (deoxyribonucleic acid) of tumor cells and blocks the function of DNA and RNA (ribonucleic acid) of tumor cells. These actions help to kill the tumor cells. Celecoxib is a drug that may help to prevent the development of some types of cancer by blocking a type of enzyme (COX-2) that is found in tumor cells. Temozolomide and CCNU are the current standard treatment for malignant brain tumors. Both drugs work by damaging the DNA (deoxyribonucleic acid) of tumor cells to kill these tumor cells. 6-Thioguanine is a drug that helps to increase the effects of Temozolomide and CCNU on tumor cells.

This study, NCT00504660, has the following objectives:
Primary Objectives:

To determine the efficacy, as measured by 12 month progression-free survival, of Temozolomide or CCNU with 6-Thioguanine followed by Capecitabine and Celecoxib in the treatment of patients with recurrent and/or progressive anaplastic gliomas or glioblastoma multiforme.
To determine the long-term toxicity of Temozolomide or CCNU with 6-Thioguanine followed by Capecitabine and Celecoxib in recurrent anaplastic glioma or glioblastoma multiforme patients treated in this manner.
To determine the clinical relevance of genetic subtyping tumors as a predictor of response to this chemotherapy and long term survival.

However, the question is about Xeloda alone. I understand that the otehr drugs have been approved.

Xeloda is also being investigated with radiation and in combination with other chemotherapy drugs for glioblastoma. Several trials are lsited on: http://clinicaltrials.gov/ct2/results?recr=Open&term=glioma

http://clinicaltrials.gov/ct2/show/NCT00504660?term=glioma&recr=Open&rank=12

nccn.org, brain cancer

A. Reardon, Patrick Y. Wen Therapeutic Advances in the Treatment of Glioblastoma: Rationale and Potential Role of Targeted Agents The Oncologist, Vol. 11, No. 2, 152-164, February 2006

Of the 22 studies that measured diagnostic performance, the largest head-to-head comparison of MR imaging alone versus MR imaging and 1H-MR spectroscopy provided encouraging findings that 1H-MR spectroscopy can make a significant contribution to diagnosis for patients with indeterminate brain lesions.
A number of large diagnostic performance studies have demonstrated that 1H-MR spectroscopy can accurately distinguish between high- and low-grade astrocytomas. This work now needs to be extended to demonstrate: (1) diagnostic thresholds selected a priori, rather than post hoc, can achieve similar diagnostic accuracy, (2) the incremental diagnostic yield of 1H-MR spectroscopy compared with anatomic MR imaging, and (3) that any improvement in tumor grading by 1H-MR spectroscopy leads to a reduction in biopsy rates or changes in therapy. Evidence in other clinical subgroups, such as the use of 1H-MR spectroscopy to distinguish neoplastic and non-neoplastic lesions or to differentiate recurrent tumors from radiation necrosis, is limited by the small number of studies.

W. Hollingwortha, L.S. Medinac, R.E. Lenkinskid, D.K. Shibataa, B. Bernalc, D. Zurakowskie, B. Comstockb and J.G. Jarvika A Systematic Literature Review of Magnetic Resonance Spectroscopy for the Characterization of Brain Tumors American Journal of Neuroradiology 27:1404-1411, August 2006

Moller-Hartmann W, Herminghaus S, Krings T, et al. Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 2002;44:371–81

Smith EA, Carlos RC, Junck LR, et al. Developing a clinical decision model: MR spectroscopy to differentiate between recurrent tumor and radiation change in patients with new contrast-enhancing lesions. AJR Am J Roentgenol. 2009;192(2):W45W52.

Sundgren PC, MR spectroscopy in radiation injury.AJNR Am J Neuroradiol. 2009 Sep;30(8):1469-76.

Vectibix is a recombinant, human IgG2 kappa monoclonal antibody that binds specifically to the human Epidermal Growth Factor Receptor (EGFR). Vectibix is specifically indicated for for the treatment of EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan- containing chemotherapy regimens.

Vectibix™ treatment can cause diarrhea and, in combination with irinotecan, appears to increase the incidence and severity of chemotherapy-induced diarrhea. Amgen recently discontinued a trial due to toxicity, the phase IIIb Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial is a disappointing setback. PACCE was evaluating the addition of Vectibix to a regimen of standard oxaliplatin- or irinotecan-based chemotherapy and bevacizumab. It was halted after preliminary review of data from a pre-planned interim efficacy analysis, scheduled after the first 231 events (death or disease progression), revealed a statistically significant difference in progression-free survival (PFS) and overall survival in favor of the control arm and higher toxicity in the Vectibix arm. Total enrollment of this trial had reached 1,054. Amgen is continuing phase III trials of Vectibix as a single biologic combined with chemotherapy as a first- or second-line treatment. No other clinical trials are being modified at this time, however, Amgen is evaluating data across all trials. Vectibix is approved as a third line treatment for metastatic, refractory CRC expressing EGFR. I was not able to find any trials on Vectibix and irinotecan.

Wainberg Z, Hecht JR Panitumumab in colon cancer: a review and summary of ongoing trials. Expert opinion on biological therapy. 2006 Nov;6(11):1229-35.

Saif MW, Cohenuram M Role of panitumumab in the management of metastatic colorectal cancer. Clinical Colorectal Cancer 2006 Jul;6(2):118-24

Gibson TB, Ranganathan A, Grothey A Randomized phase III trial results of panitumumab, a fully human anti-epidermal growth factor receptor monoclonal antibody, in metastatic colorectal cancer. Clinical colorectal cancer 2006 May;6(1):29-31.

Tyagi P Recent results and ongoing trials with panitumumab (ABX-EGF), a fully human anti-epidermal growth factor receptor antibody, in metastatic colorectal cancer Clinical colorectal cancer 2005 May;5(1):21-3.

Vectibix, prescribing information

Camacho L LH Novel therapies targeting the immune system: CTLA4 blockade with tremelimumab (CP-675,206), a fully human monoclonal antibody. Expert opinion on investigational drugs 2008 Mar 1; 17(3):371-85

Keilholz, Ulrich CTLA-4: Negative Regulator of the Immune Response and a Target for Cancer Therapy. Journal of Immunotherapy. 31(5):431-439, June 2008.

This phase II trial is studying how well giving AZD6244 and erlotinib hydrochloride together works in treating patients with locally advanced or metastatic pancreatic cancer that is refractory to gemcitabine hydrochloride.

The approach is promising but remains experimental at this time.

CLINICAL SUMMARY:

61 year-old woman with unresectable pancreatic cacner who ahd been on gemcitabien and capecitabine and progressed. Now proposed is

REFERENCES

Caroline H Diep et al, Synergistic effect between erlotinib and MEK inhibitors in KRAS wildtype human pancreatic cancer cells, Clinical Cancer Research, http://clincancerres.aacrjournals.org/content/early/2011/03/05/1078-0432.CCR-10-2214

Shivanni Kummar, Helen X. Chen, John Wright, Susan Holbeck, Myrtle Davis Millin, Joseph Tomaszewski, James Zweibel, Jerry Collins & James H. Doroshow  Utilizing targeted cancer therapeutic agents in combination: novel approaches and urgent requirements, Nature Reviews Drug Discovery 9, 843-856 (November 2010)

Drugs used in chemotherapy, such as docetaxel and prednisone, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. It is not yet known whether docetaxel, prednisone and bevacizumab are more effective than docetaxel and prednisone in treating prostate cancer.

Findings from a recent phase II trial have shown that a combination of provange and avastin may be beneficial for patients with prostate cancer. The study population consisted of 22 patients who had androgen depended prostate cancer and was having increasing levels of PSA. All patients had undergone previous definitive treatment either in the form of radiation therapy or surgery. All patients received a combination of APC8015 (provenge) in combination with avastin. The treatment was continued until patient had either disease progression or intolerable side effects. The FDA followed ODAC’s recommendation against Provenge.

Out of 22 patients 21 were evaluable for end points of the study. The median PSA doubling time in these patients was 6.7 months and median time on treatment was 12.7 months. No patients on the study had objective disease progression (onset of measurable bone or soft tissue metastasis). Four patients could not continue with the study due to toxicities and were removed from the study.

The results of a CALGB trial indicate that Avastin™/Taxotere® and estramustine can be administered safely and effectively in patients with hormone-refractory prostate cancer. The median age of the patients in this trial was 73 years, and the median PSA at study entry was 128 ng/dl. Of the 79 evaluable patients treated, 45% had measurable soft tissue lesions while 85% had a positive bone scan. Thromboembolic events (6%) were reported in 5 patients; one patient succumbed to a pulmonary embolus. Measurable disease responses were observed and 42% of patients, while 79% of patients evidenced a >50 percent PSA decline. The median time to progression has not yet been reached, and the median survival reported was approximately 20 months. The rate of thromboembolic events with this combination appears to be similar to what has been reported for other estramustine/taxane studies. Avastin alone is in a phase II trial.

There is an ongoig randomized phase III trial that is studying docetaxel, prednisone and bevacizumab to see how well they work compared to docetaxel and prednisone in treating patients with prostate cancer that did not respond to hormone therapy. Other combination trials are also being launched.

http://www.slhn-lehighvalley.org/body.cfm?id=700#CTSU90401

http://www.clinicaltrials.gov/ct/gui/show/NCT00089609

Picus J, Halabi S, Rini B, et al. The use of bevacizumab (B) with Taxotere (D) and estramustine (E) in hormone refractory prostate cancer (HRPC): Initial results of CALGB 90006. Proceedings from the 39th annual meeting of the American Society of Clinical Oncology, May 2003.Abstract 1578.

nccn.org, prostate