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PRESENTING CLINICAL TRIALS FOR PATIENT

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PRISM: a study of second-line panitumumab monotherapy for treatment of advanced head and neck cancer
David R. Spigel, MD | Sarah Cannon Research Institute, Nashville, TN
Patients with advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN) generally have a poor prognosis, with a 5-year survival rate of 15%30%. First-line therapy for locoregionally recurrent or metastatic SCCHN typically consists of cisplatin combined with 5-fluorouracil or docetaxel, but even with treatment, median time to disease progression is short. Few effective second-line therapy options exist for patients with recurrent or refractory disease. Panitumumab is a novel fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR). It is approved as a single agent for the treatment of metastatic colorectal cancer. In patients with advanced SCCHN, EGFR inhibition potentially may have a clinical benefit. An ongoing open-label phase II trial known as PRISM (Panitumumab Regimen in Second-line Monotherapy of Head and Neck Cancer) is evaluating the efficacy and safety of panitumumab monotherapy for second-line treatment of metastatic or recurrent SCCHN.

atients with metastatic or recurrent squamous cell carcinoma of the head and neck (SCCHN) have a poor prognosis. Median survival ranges from 6 to 9 months, and the 5-year survival rate is less than 30%.13 Standard treatment with 5-fluorouracil (5-FU) or a taxane in combination with a platinum agent yields response rates of up to 40% but has little impact on survival. Patients with metastatic SCCHN who do not respond to first-line therapy or experience recurrent disease have a median survival of 34 months, even with chemotherapy.4 The lack of effective treatment options in the second-line setting underscores the need for new therapeutic approaches for such patients.
A SUPPLEMENT TO9/Supplement 11 Volume 5/Number COMMUNITY ONCOLOGY

What is the rationale for EGFR inhibitor therapy in SCCHN? The epidermal growth factor receptor (EGFR; also known as HER1 or erbB1) is a member of the
Correspondence to: David R. Spigel, MD, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203; telephone: 615-329-7274; fax: 615-986-0029; email: dspigel@tnonc.com. Acknowledgments: This study is sponsored by Amgen. This manuscript and associated publication costs were funded by Amgen. The author thanks Larry J. Rosenberg, PhD, at Elsevier Oncology for medical writing support and Elsevier Oncology and Amgen for editorial support. The author, David R. Spigel, MD, was responsible for providing final approval to publish.
Commun Oncol 2008;5(suppl 11):14 2008 Elsevier Inc. All rights reserved.

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Resources
Information on eligibility for this clinical trial and treatment:

Amgen Clinical Trials: www.amgentrials.com/ t_index.cfm?did=2627&cid=4 National Institutes of Health: www.clinicaltrials. gov/ct2/show/ NCT00446446 National Cancer Institute: www.cancer.gov/ cancertopics/types/head-and-neck/ American Cancer Society: www.cancer.org The Yul Brynner Head and Neck Cancer Foundation: www.headandneck.org MedlinePlus: Head and Neck Cancer: www. nlm.nih.gov/medlineplus/headandneckcancer. html The American Academy of Otolaryngology: www.entnet.org/HealthInformation/ headNeckCancer.cfm American Head and Neck Society: www. headandneckcancer.org Coalition of Cancer Cooperative Groups: www.cancertrialshelp.org Cancer Trials Support Unit: www.ctsu.org

Patients seeking general information:

HER family of growth factor receptors. The EGFR is a key regulator of cell growth, repair, differentiation, apoptosis, angiogenesis, and malignant transformation.5 Most SCCHN tumors express the EGFR as well as its ligand, transforming growth factor alpha (TGF-).4,69 EGFR overexpression is correlated with resistance to chemotherapy and radiation therapy and predicts for a worse diseasefree and overall survival. The EGFR is thus a rational target for therapy in EGFR-expressing tumors such as SCCHN. Two classes of EGFR inhibitors have been developed for such therapy: monoclonal antibodies, such as cetuximab (Erbitux) and panitumumab (Vectibix), and small-molecule tyrosine kinase inhibitors (TKIs),
Panitumumab monotherapy, 9 mg/kg every 3 weeks

such as gefitinib (Iressa) and erlotinib (Tarceva). EGFR-specific monoclonal antibodies and TKIs have been evaluated in combination with chemotherapy in SCCHN, based upon preclinical data suggesting that these inhibitors may synergize with other anticancer therapies. In a phase II trial involving 48 patients with recurrent or metastatic disease, the combination of erlotinib plus cisplatin and docetaxel (Taxotere) resulted in an overall response rate of 68%.10 Similarly, treatment with cetuximab plus platinum-based chemotherapy produced a 10% response rate and a tumor growth control rate of 53% in patients with platinum-refractory metastatic or recurrent disease.11 In another study of previously treated patients, cisplatin plus cetuximab was administered if less than a partial response had been achieved with prior cisplatin-based therapy.12 The combination of cisplatin and cetuximab resulted in responses in 20% of patients whose disease had progressed after first-line cisplatinbased chemotherapy and 18% of those with previously stable disease. What is panitumumab? Panitumumab is a fully human monoclonal antibody that binds to the extracellular ligand-binding domain of the EGFR. By blocking binding of natural ligands to the EGFR, panitumumab inhibits the function of the receptor. This results in blockade of EGFR-mediated signaling pathways, causing G1/G0 cell-cycle arrest, growth inhibition, and apoptosis.13 Clinical trials Panitumumab was found to be ac-

50 patients with platinum-refractory recurrent or metastatic SCCHN

Tumor assessment

Progressive disease

FIGuRE 1 Treatment schema of the PRISM trial (Amgen study 20062088). SCCHN = squamous cell carcinoma of the head and neck

tive in phase I and II trials in patients with metastatic colorectal cancer (mCRC) who had failed to respond to prior cytotoxic chemotherapy.1416 These observations led to a phase III randomized trial of panitumumab plus best supportive care (BSC) compared with BSC alone in patients with mCRC whose disease had progressed on cytotoxic chemotherapy.17 Compared with BSC alone, patients on the panitumumab arm experienced a significantly prolonged progressionfree survival (8 weeks vs 7.3 weeks; hazard ratio, 0.54; 95% confidence interval, 0.440.66; P < 0.0001) and overall response rate (10% vs 0%; P < 0.0001). No statistically significant increase in overall survival was observed; however, 74% of the patients receiving BSC alone crossed over to an optional trial allowing for the administration of panitumumab at the time of disease progression. In this study, panitumumab activity was found to be limited to those mCRC patients whose tumors expressed wild-type KRAS; the response rate was 17% versus 0% in patients with tumors with KRAS mutations. The progression-free survival was longer for patients with wild-type KRAS tumors treated with panitumumab at 16 weeks versus 8 weeks for patients randomized to receive BSC (based upon an interval-censored sensitivity analysis performed to compensate for potential tumor-ascertainment bias in favor of the BSC arm, whereby radiologic event times were moved to the closest assessment time prespecified in the protocol).18 Whether the presence of wild-type KRAS is also associated with response to panitumumab in patients with SCCHN tumors is unknown. Overexpression of HRAS appears to be fairly common in SCCHN tumors, although KRAS mutations are infrequent.19 The most common toxicities observed with panitumumab monotherapy in patients with mCRC were skin toxicity (all grades, approximatewww.CommunityOncology.net

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CURRENT CLINICAL TRIALS

TablE 1

Panitumumab dosage adjustments for skin and nail toxicity in the PRISM trial
Dose of panitumumab may be withheld due to skin- or nail-related toxicities:

Requiring narcotic analgesics or systemic corticosteroids or intolerable for the patient Infection requiring IV antibiotic or IV antifungal treatment Need for surgical debridement Serious adverse event

lic event in one patient (5%). These preliminary results suggest that panitumumab, in combination with carboplatin and radiation therapy, may potentially be effective for treatment of patients with advanced SCCHN. A phase I study demonstrated that panitumumab could be administered on various schedules (weekly or every 23 weeks) with equivalent pharmacokinetics and tolerability.24 What is the PRISM trial? PRISM (Panitumumab Regimen in Second-line Monotherapy of Head and Neck Cancer) is a nonrandomized, open-label, multicenter phase II study designed to evaluate singleagent panitumumab as second-line therapy in patients with platinumrefractory recurrent or metastatic SCCHN (Figure 1). In this trial, all patients will receive panitumumab at a dose of 9 mg/kg administered IV over 1 hour 15 minutes every 21 days 3 days. Treatment will be continued until disease progression, as measured by tumor assessment (modified Response Evaluation Criteria in Solid Tumors), or unacceptable toxicity, study withdrawal, death, or end of study. Panitumumab administration may be withheld due to skin- or nail-related toxicity and can be subsequently resumed after resolution of symptoms or when systemic treatment for such toxicity is no longer required (Table 1). The primary study endpoint for the PRISM trial is overall response rate. Secondary endpoints include time to tumor response, duration of response, rate of disease control, time to disease progression, progression-free survival, overall survival, and safety. With a target enrollment of 50 patients, the study will have 90% power to distinguish no activity from a 12% response rate. A response rate of 10%15% is anticipated. Key eligibility criteria for this trial include histologically or cytologically confirmed SCCHN of the orophar-

TablE 2

Key eligibilty criteria for the PRISM trial

Inclusion criteria

Men or women aged 18 years or older Metastatic or recurrent disease, histologically or cytologically confirmed SCCHN of the oropharynx, oral cavity, hypopharynx, or larynx Metastatic or recurrent disease determined to be incurable by surgery or radiotherapy Measurable disease, as determined by computed tomography or magnetic resonance imaging Documented disease progression or intolerance to chemotherapy following treatment with only one prior platinum-based chemotherapy regimen for metastatic or recurrent disease Radiation as primary therapy if locoregional tumor recurrence in the field occurred 24 weeks after therapy Karnofsky Performance Status of 60% at screening Adequate hematologic, hepatic, and renal function Documented or symptomatic CNS metastases, nasopharyngeal carcinoma, salivary gland, or primary skin SCCHN, or a history of another primary cancer Clinically significant active cardiovascular disease 24 weeks prior to enrollment, or pulmonary embolism, deep vein thrombosis, or other significant thromboembolic event 8 weeks prior to enrollment History of severe skin disorder Prior treatment with more than one chemotherapy regimen for metastatic or recurrent disease* Prior therapy with epidermal growth factor receptor (EGFR) inhibitors (eg, panitumumab, cetuximab, gefitinib, erlotinib, lapatinib) for recurrent or metastatic disease unless: Prior EGFR therapy was received as part of multimodality treatment and completed 24 weeks before randomization Patient received no more than one dose of cetuximab that was discontinued before progression due to a documented severe infusion reaction Major surgery requiring general anesthesia/ spinal anesthesia and a significant incision 28 days prior to enrollment History of interstitial lung disease, significant cardiovascular disease, or another primary cancer Significant thromboembolic event 8 weeks prior to enrollment Use of immunosuppressive agents (corticosteroids are allowed)

Panitumumab administration may resume once:

Adverse event has improved to grade 2 or baseline Tolerable for the patient Systemic corticosteroids, narcotic analgesics, IV antibiotics, or IV antifungals are no longer required

Exclusion criteria

ly 90%; grade 3 or 4, 16%) and diarrhea (all grades, 21%; grade 3 or 4, 2%).20 Dermatologic effects include acneiform rash, eczema, hair and nail changes, telangiectasia, hyperpigmentation, and fissures.21,22 In addition to dermatologic toxicities, other reported treatment-related grade 3/4 adverse effects include nausea, vomiting, and fatigue.13 Panitumumab therapy in advanced SCCHN Panitumumab has shown efficacy in clinical trials for patients with advanced SCCHN. An initial phase I study of this agent was conducted in 19 treatment-naive patients with stage III/IV disease.23 Panitumumab (2.5 mg/kg) was administered with weekly carboplatin (AUC [area under the concentration-vs-time curve] 1.5) plus intensity-modulated radiotherapy (70 Gy). Of the 15 patients evaluable for response, 13 (87%) had a complete response. Severe adverse events included grade 3 dysphagia (95%), grade 3/4 mucositis (89%), grade 2/3 acneiform rash (79%), grade 3 radiation dermatitis (37%), grade 3 nausea (5%), and grade 4 sepsis and a thromboemboVolume 5/Number 9/Supplement 11

* Concomitant chemotherapy for recurrent disease given solely for radiation sensitization during reirradiation is not counted toward the above regimen.

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ynx, oral cavity, hypopharynx, or larynx; recurrent or metastatic disease not curable by surgery or radiation therapy; documented disease progression or intolerance to chemotherapy after no more than one prior chemotherapy regimen for recurrent/metastatic disease; radiation as primary therapy if locoregional tumor recurrence in the field occurred 24 weeks after therapy; at least one measurable lesion of 20 mm using conventional techniques or 10 mm with spiral CT; Karnofsky Performance Status of at least 60 at baseline; and adequate hematologic, hepatic, and renal function. Key exclusion criteria include central nervous system metastases; nasopharyngeal carcinoma, salivary gland, or primary skin SCCHN; history of another primary cancer; prior treatment with more than one chemotherapy regimen for metastatic or recurrent disease; clinically significant, active cardiovascular disease or other thromboembolic event prior to enrollment; prior EGFR inhibitor therapy for recurrent or metastatic disease, unless treatment with an EGFR inhibitor was received as a part of a prior multimodality treatment regimen and completed at least 24 weeks prior to randomization; and history of a severe skin disorder. Key inclusion and exclusion criteria are listed in Table 2. The PRISM study will be conducted at approximately 40 sites in North America and Australia. Accrual for this trial began in October 2007 and is currently ongoing. Information on how to enroll patients or to obtain further details about the trial can be found in the accompanying box and in the following section. How can community oncologists enroll patients in the PRISM study? The PRISM study is currently ongoing and actively recruiting eligible patients. For additional information about the trial and how to enroll pa4 COMMUNITY ONCOLOGY September 2008

tients, community oncologists may: Review a complete description of the trial and a list of study locations at the National Institutes of Healths Web site, www.clinicaltrials.gov/ct2/ show/NCT00446446. Call the study sponsor, Amgen, toll-free at 1-866-572-6436 and ask about the PRISM trial (Amgen study 20062088).
References

1. American Cancer Society. Cancer Facts & Figures 2008. Atlanta, Ga: American Cancer Society; 2008. 2. Cohen EE, Lingen MW, Vokes EE. The expanding role of systemic therapy in head and neck cancer. J Clin Oncol 2004;22:17431752. 3. Lu C, Kies M. Systemic therapy for recurrent and metastatic diseases. In: Harrison LR, Sessions RB, Hong WK (eds). Head and Neck Cancer. 2nd ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2003:919925. 4. Cohen EE. Role of epidermal growth factor receptor pathway-targeted therapy in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 2006;24:26592665. 5. Harari PM, Allen GW, Bonner JA. Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol 2007;25:4057 4065. 6. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993;53:35793584. 7. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res 2002;62:73507356. 8. Pivot X, Magne N, Guardiola E, et al. Prognostic impact of the epidermal growth factor receptor levels for patients with larynx and hypopharynx cancer. Oral Oncol 2005;41:320327. 9. Chung CH, Ely K, McGavran L, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 2006;24:41704176. 10. Kim ES, Kies MS, Glisson BS, et al. Final results of a phase II study of erlotinib, docetaxel and cisplatin in patients with recurrent/ metastatic head and neck cancer. J Clin Oncol 2007;25(18S):6013. 11. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23:55685577.

12. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. J Clin Oncol 2005;23:55785587. 13. Carten G, Fiorentino R, Vecchione L, Chiurazzi B, Battista C. Panitumumab: a novel drug in cancer treatment. Ann Oncol 2007;18(suppl 6):vi, 1621. 14. Meropol NJ, Berlin J, Hecht JR, et al. Multicenter study of ABX-EGF monotherapy in patients with metastatic colorectal cancer. Proc Am Soc Clin Oncol 2003;22:1026. 15. Hetch JR, Patnaik A, Malik I, et al. Panitumumab (ABX-EGF) monotherapy in patients with metastatic colorectal cancer (mCRC): an updated analysis. J Clin Oncol 2004;23(14S):3511. 16. Malik I, Hecht JR, Patnaik A, et al. Safety and efficacy of panitumumab monotherapy in patients with colorectal cancer. J Clin Oncol 2005;23(16S):3520. 17. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 2007;25:16581664. 18. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 2008;26:16261634. 19. Kiaris H, Spandidos DA, Jones AS, Vaughan ED, Field JK. Mutations, expression and genomic instability of the H-ras proto-oncogene in squamous cell carcinomas of the head and neck. Br J Cancer 1995;72:123128. 20. Vectibix (panitumumab) prescribing information. Thousand Oaks, Calif: Amgen Inc.; 2008. 21. Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 2005;16:1425 1433. 22. Cohenuram M, Saif MW. Panitumumab the first fully human monoclonal antibody: from the bench to the clinic. Anticancer Drugs 2007;18:715. 23. Wirth LJ, Posner MR, Tishler RB, et al. Phase I study of panitumumab + chemoradiotherapy (CRT) for head and neck cancer (HNC). J Clin Oncol 2008;26(15S):6007. 24. Weiner LM, Belldegrun AS, Crawford J, et al. Dose and schedule study of panitumumab monotherapy in patients with advanced solid malignancies. Clin Cancer Res 2008;14:502 508.

abOuT THE auTHOR Affiliation: Dr. Spigel is Director of Lung Cancer Research at Sarah Cannon Research Institute, Nashville, TN. Conflicts of interest: Dr. Spigel receives funding from Amgen for the current trial.

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