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© 2001 American Society for Clinical Oncology
Phase II Trial of Intratumoral Administration of ONYX-015, a Replication-Selective Adenovirus, in Patients With Refractory Head and Neck CancerFrom US Oncology, Dallas, Baylor University Medical Center, Dallas, and M.D. Anderson Cancer Center, Houston, TX; Beatson Oncology Centre, Glasgow, Scotland; Albany Regional Cancer Center, Albany, NY; Dana-Farber Cancer Institute, Boston, MA; University of Chicago, Chicago, IL; and Onyx Pharmaceuticals, Inc, Richmond, CA. Address reprint requests to John Nemunaitis, MD, US Oncology, 3535 Worth St, Collins Bldg, 5th Floor, Dallas, TX 75246; email John. Nemunaitis{at}USOncology.com
PURPOSE: To determine the safety, humoral immune response replication, and activity of multiple intratumoral injections of ONYX-015 (replication selective adenovirus) in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: This phase II trial enrolled patients with SCCHN who had recurrence/relapse after prior conventional treatment. Patients received ONYX-015 at a dose of 2 x 1011 particles via intratumoral injection for either 5 consecutive days (standard) or twice daily for 2 consecutive weeks (hyperfractionated) during a 21-day cycle. Patients were monitored for tumor response, toxicity, and antibody formation.
RESULTS: Forty patients (30 standard and 10 hyperfractionated) received 533 injections of ONYX-015. Standard treatment resulted in 14% partial to complete regression, 41% stable disease, and 45% progressive disease rates. Hyperfractionated treatment resulted in 10% complete response, 62% stable disease, and 29% progressive disease rates. Treatment-related toxicity included mild to moderate fever (67% overall) and injection site pain (47% on the standard regimen, 80% on the hyperfractionated regimen). Detectable circulating ONYX-015 genome suggestive of intratumoral replication was identified in 41% of tested patients on days 5 and 6 of cycle 1; 9% of patients had evidence of viral replication 10 days after injection during cycle 1, and no patients had evidence of replication CONCLUSION: ONYX-015 can be safely administered via intratumoral injection to patients with recurrent/refractory SCCHN. ONYX-015 viremia is transient. Evidence of modest antitumoral activity is suggested.
THE PROGNOSIS FOR recurrent squamous cell carcinoma of the head and neck (SCCHN) region is discouraging.1,2 Local tumor progression leads to morbidity and even death in the majority of patients. Therefore, improved local and local-regional therapeutic approaches are needed. Treatment after failure of surgery and radiation therapy generally involves chemotherapy.1,2 Approximately 30% to 40% of patients with recurrent head and neck cancer respond to combination chemotherapy, which generally includes cisplatin. The duration of response is short, and median survival is less than 6 months.1-9 Furthermore, local expansion of disease during or after chemotherapy leads to devastating functional, economic, cosmetic, and psychologic effects to the patient. Because recurrence frequently occurs within a prior radiation field, further radiotherapy is not an option, and palliative surgery is generally associated with excess morbidity and additional cost, while not affecting survival. Second-line chemotherapy with other agents, such as paclitaxel, docetaxel, methotrexate, topotecan, or gemcitabine (alone or in combination), has been tested, but response rates remain poor,10-31 and the duration of the response is less than a few months.9,32,33 Therefore, novel approaches to the local control of chemotherapy resistant/refractory SCCHN are needed. ONYX-015 (dl1520) is a replication-selective adenovirus.34 Efficient adenovirus replication is dependent on the expression of proteins that inactivate p53.35,36 The normal p53 gene product inhibits viral replication. ONYX-015 is an adenovirus that has been modified by deletion of the E1B 55-kd DNA fragment. The E1B–55-kd gene product inactivates p53 in complex with E4ORF6.37 It has been hypothesized that deletion of the E1B–55-kd region enables the p53 protein to maintain its function, thereby inhibiting viral replication in cells with normal p53 function; however, in cells that lack normal p53 function, such as malignant cells, the E1B–55-kd gene product may be expendable and the cells should be susceptible to replication and killing after infection. Initial reports38 suggested that p53 mutant tumor cells could be lysed in a replication-dependent fashion both in vitro and in vivo after exposure to ONYX-015.34,39 In addition, several tumor lines containing a normal wild-type p53 gene sequence were also found to be sensitive to the oncolytic activity of ONYX-015.39-41 This finding is expected, since p53 function can be lost through multiple mechanisms besides gene mutation (eg, p53 protein binding degradation). Importantly, most groups found significantly less replicative capacity of ONYX-015 in weak normal cells compared with malignant cells,39,41,42 which suggests a possible therapeutic index to ONYX-015 in the treatment of cancer. Phase I investigation identified the toxicity of intratumoral injection of ONYX-015 to be limited to transient low-grade fever and injection site pain in one third of patients (S. Kaye, manuscript in preparation). Viral doses up to 1 x 1011 plaque-forming units (pfu) given daily once every 3 weeks, or 1 x 1010 pfu for 5 consecutive days every 3 weeks, were well-tolerated. No dose-limiting toxicity or maximum-tolerated dose was identified. Dose escalation, therefore, proceeded to the highest dose that could be practically manufactured. Additionally, multiday dosing with each dose administered to separate tumor quadrants seemed to be associated with a more effective induction of tumor necrosis over single-day dosing. Thus, we initiated a phase II investigation with ONYX-015 to be administered by intratumoral injection with multiple doses per cycles to patients with recurrent or refractory SCCHN.
Enrollment Criteria Patients were required to have histologically confirmed SCCHN (excluding nasopharyngeal) that had (1) recurred/relapsed after surgery and/or radiotherapy for the primary tumor and (2) had progressed on or within 8 weeks after completion of chemotherapy and/or radiotherapy (ie, tumors were refractory). Tumors could not be surgically curable. The tumor mass to be treated with ONYX-015 had to be adequately injectable (as defined below) and measurable (radiographically or by physical examination). Patients had to be older than 18 years old and had to have a Karnofsky performance status score of  70 and life expectancy of 3 months. Normal hematologic function and renal function were also required. A signed consent form (internal review board–approved) was required before enrollment. The p53 gene status was not used as an enrollment criterion. Institutional review board approval of the protocol and consent form was required.
Baseline Assessment
ONYX-015
Detection of ONYX-015 Adenovirus
Patient samples are spiked with exogenous DNA to monitor recovery in the extraction step and the presence of PCR inhibitors. A standard curve is prepared by serial diluting ONYX-015 virus from 2 x 109 to 1.05 x 104 vp/mL. Negative controls consist of a plasma control without virus and a type D adenovirus wild-type control. Viral DNA is extracted from patient samples, standard, and controls using a QIAamp DNA mini kit (Valencia, CA). The amount of ONYX-015 viral DNA is then quantitated by reverse transcription PCR using the above-described specific primer and probe.
ONYX-015 Handling and Processing
Treatment Regimen In the initial phase of the study, tumor injections were performed once daily for 5 consecutive days (standard schedule); these injections were repeated every 3 weeks or until tumor progression. After documentation of safety with this regimen (n = 30), a more aggressive injection regimen was tested in a subsequent 10 patients by administering a four-fold higher dose; identical injections were performed twice daily for 5 days during each of the first 2 weeks on study (hyperfractionated schedule). After a 1-week rest period, the hyperfractionated regimen was repeated. Patients’ vital signs were taken 15 minutes before and after each treatment for a minimum of 30 minutes. Patients were eligible for repeat treatment cycles at the same dosage every 3 weeks if no grade 4 toxicity with the prior treatment cycle of ONYX-015 occurred and no progression of the injected tumor was observed. After this induction regimen, maintenance treatment cycles were given by the same schedule as was used in the initial patient cohort (every 3 weeks as described above). The injections were given in outpatient clinics, including Mary Crowley Medical Research Center at Baylor University Medical Center (Dallas, TX), Albany Regional Cancer Center (Albany, NY), US Oncology Research (Houston, TX), Beatson Oncology Centre (Glasgow, Scotland), Dana-Farber Cancer Institute (Boston, MA), University of Chicago (Chicago, IL), and M.D. Anderson Cancer Center (Houston, TX).
Tumor Assessments
The degree of necrosis induction within injected tumors was categorized as follows: complete regression, complete disappearance of measurable tumor; partial regression,
p53 Gene Sequencing Determination
Determination of Neutralizing Antibody Titers
Additional Follow-Up After Treatment Initiation
Treatment Forty patients were entered onto the trial from six sites (Mary Crowley Medical Research Center at Baylor University, M.D. Anderson Cancer Center, Beatson Cancer Institute, Albany Regional Cancer Center, Dana-Farber Cancer Institute, the University of Chicago) between July 1997 and September 1998. The first 30 patients were enrolled onto the standard ONYX-015 schedule trial; the 10 patients enrolled subsequently received the hyperfractionated regimen. All patients registered received at least a single injection of ONYX-015 and were assessable for toxicity. Thirty-six patients were considered assessable for initial response. Two patients (one standard, one hyperfractionated) were not assessable due to death before response assessment (not treatment-related), and two patients (hyperfractionated) withdrew before response assessment. Characteristics of patients receiving the standard versus hyperfractionated schedule are listed in Table 1. As listed in Table 2, 70 cycles (345 doses) were administered to 30 patients who received standard-schedule ONYX-015, and 27 cycles (188 doses) were administered to 10 patients who received the hyperfractionated schedule.
Tumor Response Data on the response of injected tumors is listed in Table 3. Four patients (14%) who received the standard dosing schedule achieved a partial or complete regression of the injected tumor, 12 (41%) had stable disease, and 13 (45%) progressed. One (14%) of the hyperfractionated patients achieved a complete regression, four (58%) achieved stable disease, and two (29%) progressed. The median time to injected tumor progression, progression-free survival, and survival with the standard versus hyperfractionated approaches are listed in Table 3. No significant differences were observed between the two dosing regimens. There was no correlation between baseline tumor area, neutralizing antibody level, and response. A significant correlation was demonstrated between antitumoral activity (complete, partial, and minor responses) and presence of a p53 gene mutation (P = .017).
Toxicity Toxicity that occurred in more than 25% of patients is listed in Table 4. The majority of the toxic effects were of mild or moderate intensity. Fatal toxicity not related to ONYX-015 occurred in three standard-treatment patients (10%) and one hyperfractionation-treated patient (10%). One fatality was related to hematemesis from an unrelated gastrointestinal ulcer, one was due to hemorrhage from local progression, one was due to bacterial-induced septic shock, and one was due to anoxia caused by airway obstruction from progressive disease. Fourteen serious adverse events were reported in the standard arm, and nine serious adverse events occurred in the hyperfractionated arm. One serious adverse event was categorized as "probably related" to study medication in the standard arm (hemorrhage at injection site). The following events were categorized as possibly related to ONYX-015 injection: pneumonia with no organisms identified (n = 1), confusion (although concurrent hypocalcemia may have been related; n = 1), and recurrent atrial flutter (n = 1). The other 10 serious adverse events were either not related or the relationships were unable to be determined. Among patients who received hyperfractionated treatment, one patient developed injection site hemorrhage categorized as possibly related to ONYX-015 injection. Other events were categorized as not related or unable to be determined. Nine of 40 patients developed pneumonia not related to study treatment (six standard and three hyperfractionated). A specific cause of pneumonia was identified in three patients (two bacterial and one unrelated peptic ulcer perforation). The six other causes were thought to be related to aspiration associated with the cancer. The pneumonia lasted from 6 to 13 days. Six patients were retreated with ONYX-015 after resolution of pneumonia without recurrence. Reasons for study discontinuation are listed in Table 5.
Systemic Distribution of ONYX-015 All 30 patients (29 of 30 in cycle 1) in the standard arm were tested for circulating ONYX-015 using PCR analysis 24 hours after the 5-day intratumoral injection series. Previous studies have shown rapid clearance of the ONYX-015 genome from the blood (approximately 6 hours); therefore, viremia 24 hours after the last injection is strong evidence for viral replication and shedding. Detectable levels of ONYX-015 were identified in 12 (41%) of 29 patients 24 hours after the last ONYX-015 injection (Table 6). In two patients (9%), the ONYX-015 genome was detected 10 days after injection in cycle 1. No samples were positive for circulating ONYX-015 genome 22 days after any injection in cycle 1 or any other cycle, and 15 days after any injection beyond cycle 1. Six (28%) of 21 patients had detectable circulating ONYX-015 genome in cycle 2 24 hours after intratumoral injection, and two of eight patients had detectable circulating ONYX-015 genome 24 hours after injection in cycle 3. The two patients who had detectable ONYX-015 genome in cycle 3 achieved a minor response and a complete response. Otherwise no correlation between circulating genome and response was observed in patients with detectable genome in cycle 2 or patients with circulating genome in cycle 1. Patients entered onto the hyperfractionated treatment arm were not followed for systemic distribution of ONYX-015 genome.
Neutralizing Antibody Titers Sixteen patients who received standard ONYX-015 and seven patients who received hyperfractionated ONYX-015 were identified as having high (elevated > 1:20) neutralizing antibody titers at baseline (Table 1). Fifty-three percent of standard-arm patients had antibody titers more than 1:20 at baseline, and 23 (96%) of 24 patients measured after cycle 1 had antibody titers above 1:20. All patients in the standard arm had neutralizing antibody titers above 1:20 after cycle 2. The median antibody titers at baseline (n = 30) was 51 (range, 0 to 1,798). After cycle 1 (n = 24), the median titer was 11,896 (range, 0 to 81,920). After cycle 2 (n = 14), the median titer was 12,363 (range, 225 to 71,425). Similar titers were seen in the hyperfractionation-treated patients. At baseline (n = 9), the median neutralizing titer was 1,074 (range, 0 to 8,847). This increased to 9,733 (range, 2,165 to 62,700) after cycle 2 (n = 5). There was no correlation of baseline titer levels to tumor response, time to local progression, progression-free survival duration, or overall survival.
The results from these trials indicate that intratumoral injection of the replication-selective adenovirus ONYX-015 at a dose of 1 x 1010 pfu daily for 5 days of a 21-day cycle was well tolerated. Transient low-grade fever and injection site pain were the most frequent toxicities. These were manageable on an outpatient basis. Antitumor activity (as measured by 50% tumor destruction) was observed in approximately 14% of patients and did not seem different between the standard and hyperfractionation arms. Survival was also not different between the two arms; however, injection site pain occurred more frequently on the hyperfractionated regimen. Future proof of clinical benefit will be necessary to determine clinical utility. These data suggest that ONYX-015 has a favorable safety profile and modest efficacy in recurrent head and neck cancer as a single agent. Future testing in this patient population has, therefore, focused on combinations with standard agents, such as cisplatin-based chemotherapy.43 Replication-competent viruses have been tested as therapeutic agents for more than 100 years. Smallpox was eradicated with a replicating virus vaccine.44,45 Exploration of the use of replicating viruses for the treatment of cancer was documented as early as 1912 when a woman with advanced cervical cancer achieved a response after injection with an attenuated rabies virus.46,47 In 1950, the oncolytic activity of Egypt 101 virus was validated in vitro,48 and clinical activity was suggested after intratumoral injection in cancer patients.49-51 However, the antitumoral effects were transient (< 3 months). Subsequent clinical investigation with mumps virus as a cancer therapy was reportedly associated with a 41% "response" rate in 90 treated patients.52 However, a follow-up trial53 involving 200 cancer patients in whom mumps virus was administered by a multiple intratumoral injection schedule revealed transient tumor regression in only 26 patients. Toxicity was limited to transient fever and injection site pain. Another oncolytic virus, Newcastle disease virus (NDV),54-58 showed selective replicative capacity in malignant cells. The mechanism of NDV selectivity may be related to elevated myc oncogene expression or differences in membrane permeability, as opposed to the E1B–55-kd deletion effect on p53 with ONYX-015.58-60 Additionally, consistent with what we observed with ONYX-015, tumor response was correlated with viral replication–induced oncolysis.57 NDV was used to lyse tumor cells in vitro for the purpose of creating a viral oncolysate (virus and lysed tumor cells). Several trials in melanoma patients with limited-stage disease undergoing surgical resection followed by vaccination with the NDV viral oncolysate suggested improved survival compared with historical controls.61-64 Similar results have been found in separate trials involving patients with colorectal carcinoma,65 advanced renal cell carcinoma,66 metastatic breast cancer, and ovarian cancer.67 Influenza virus and vaccinia virus have also been studied as a viral oncolysate for tumor vaccine trials.68-70 More recently, a variety of replication-selective viruses have been either engineered for replication selection (including human adenovirus, herpes virus, and vaccinia virus)71 or shown to be replication-selective based on specific genetic tumor target (ie, activated ras for retrovirus).72-75 Replication-selective, tumor-targeting bacteria such as Salmonella typhimurium have also shown encouraging preclinical activity. A great deal of data have been accumulated suggesting that adenovirus serotype 5 is an effective oncolytic virus with a low toxicity profile to humans. DNA from thousands of human tumors have been analyzed for the presence of adenovirus DNA, and no integrated viral DNA has been isolated from any human tumor.72 Eighty percent of adults have existing antibodies to adenovirus serotype 5, but less than 15% of exposed patients become clinically symptomatic.73 The most common symptoms of an adenoviral serotype 5 infection are flu-like in nature and include cough, gastroenteritis, conjunctivitis, and, rarely, pneumonia. However, these symptoms are rarely seen even in immunocompromised patients.74 Oral adenoviral vaccines were given to thousands of military recruits in the 1960s without adverse effects or increase in cancer.75 Long- and short-term safety of intratumoral adenoviral injection has been shown in several animal cancer models,76-82 and live adenovirus inocula were given intratumorally and intra-arterially to patients with cervical carcinoma at the National Cancer Institute in the 1950s.51 Again, no significant toxicities, other than transient fever and malaise, were observed, even in subsets of patients treated with corticosteroids and in those in whom neutralizing adenovirus antibodies were not present. Intravascular administration was also well tolerated in a small group of patients.83 Adenoviral vectors with the E1 and E3 deletion containing the Escherichia coli cytosine deaminase gene have also been administered via intradermal injection to normal individuals in studies of toxicity and immune response at dose levels of 106, 107, and 108 pfu.84 No significant toxicity was observed.84 This was consistent with clinical trial results in the same patient population of head and neck cancer patients described in this trial who received a nonreplicating adenoviral vector containing a wild-type p53 gene.85,86 Given the safety and toxicity profile of ONYX-015, it seems reasonable to explore this virus in patients with earlier-stage disease87-90 and possibly even to enhance sensitivity when combined with chemotherapy or radiation therapy.39 Independent of the ONYX-015 replication-induced oncolysis, ONYX-015 E1A gene expression can activate the cell cycle and increase cellular sensitivity to chemotherapy or radiation therapy. Use of ONYX-015 for local management of SCCHN and as adjuvant therapy after surgical resection of SCCHN and, possibly, other malignant tumors should also be considered but will require further investigation. Comparison of survival between responding and nonresponding patients will also need to be followed in the future, although differences observed in this trial were not significant. Pursuit of other schedules of intratumoral administration (ie, > 5 days/21-day course) are unlikely to be of value, although justification of a systemic infusion schedule for ONYX-015 may be warranted since it has been shown to be safe and efficacious in animal cancer models.39 Detection of ONYX-015 genome in plasma on the last day of ONYX-015 injection suggests that circulating virus, at low plasma concentration, is safe. Furthermore, persistent detection in two patients 10 days after the last injection suggests that a viral replicative process was ongoing, although it did not persist since none of the samples tested showed evidence of circulating viral genome more than 17 days after the last injection. Future work with ONYX-015 and other replication-selective viruses will also explore the possibility of arming these viruses with exogenous genes, particularly if selective tumor replication is confirmed. Antitumor effects correlating with enhanced cytotoxic T-lymphocyte activity have been noted in vivo with replication-selective herpes simplex virus (G207) carrying an interleukin 12 gene,71 for example. Over the next year, a number of these replication-selective agents are expected to enter clinical testing.
The authors thank Ana Petrovich for manuscript preparation, Angela Buchanan for analysis interpretation, Sherry Toney for extensive time and effort in coordinating study samples and results as well as editorial proofing of the manuscript, and Carrie LeDuc from Althea for her assistance with sequence interpretation and for providing the methods discussion for sequencing.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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