Journal of Thoracic Oncology:
A Phase I Trial of the HIV Protease Inhibitor Nelfinavir with Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-small Cell Lung Cancer: A Report of Toxicities and Clinical Response
Rengan, Ramesh MD, PhD*; Mick, Rosemarie MS,†; Pryma, Daniel MD‡; Rosen, Mark A. MD, PhD‡; Lin, Lilie L. MD*; Maity, Amit M. MD, PhD*; Evans, Tracey L. MD§; Stevenson, James P. MD§; Langer, Corey J. MD§; Kucharczuk, John MD║; Friedberg, Joseph MD║; Prendergast, Susan BS, RN*; Sharkoski, Tiffany BA*; Hahn, Stephen M. MD*
*Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
†Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
‡Division of Nuclear Medicine, Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
§Division of Hematology-Oncology, Department of Internal Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
║Division of Thoracic Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
Disclosure: Ramesh Rengan, MD, PhD, has received a grant from the American Society for Radiation Oncology (ASTRO). Rosemarie Mick, MS, has received a grant from the NIH (R21-CA144190). Tracey L. Evans, MD, has served as a consultant for Genentech, occassionally receives payment for speaking, and is emplyed by the University of Pennsylvania. James P. Stevenson, MD, serves as a board member for GlaxoSmithKline, has received a rant from Imclone, has a grant pending from Eli Lilly, and has received payment for lectures from Eli Lilly and Genentech.
Address for correspondence: Ramesh Rengan, MD, PhD, University of Pennsylvania, 3400 Civic Center Blvd., TRC 2 West, Philadelphia, PA, 19104. E-mail: email@example.com
Background: The objective of this phase I trial was to determine dose-limiting toxicities (DLT) and the maximally tolerated dose of the radiosensitizer Nelfinavir in combination with concurrent chemoradiotherapy in locally advanced non-small cell lung cancer (NSCLC).
Methods: Nelfinavir (dose level 1: 625 mg orally [PO] twice a day; dose level 2: 1250 mg PO twice a day) was administered for 7 to 14 days before and concurrently with concurrent chemoradiotherapy to patients with biopsy confirmed IIIA or IIIB unresectable NSCLC. Five patients were treated at dose level 1; eight patients were treated at dose level 2. Patients were treated with concurrent chemoradiotherapy to a dose of 66.6 Gy. DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis.
Results: Sixteen patients were enrolled and 13 patients received at least one dose of nelfinavir. Twelve patients were treated with nelfinavir and concurrent chemoradiotherapy. No DLTs have been observed at either dose level. The maximum tolerated dose of nelfinavir was therefore 1250 mg PO twice a day. Six patients experienced grade 4 leukopenia. One patient experienced grade 4 thromobcytopenia. Median follow-up for all 12 response-evaluable patients was 31.6 months and for survivors is 23.5 months. Nine of the 12 patients had evaluable posttreatment positron emission tomography/computed tomography with metabolic response as follows: overall response: 9/9 (100%); complete response: 5/9 (56%); and partial response: 4/9 (44%).
Conclusion: Nelfinavir administered with concurrent chemoradiotherapy is associated with acceptable toxicity in stage IIIA/IIIB NSCLC. The metabolic response and tumor response data suggest that nelfinavir has promising activity in this disease.
Approximately 50,000 patients are diagnosed annually with stage III non-small cell lung cancer (NSCLC). Five-year survival is extremely poor at 15 to 40%.1 A standard therapeutic approach for patients with unresectable stage IIIA disease is definitive radiotherapy to a dose of 60 to 70 Gy given concurrently with a platin-based regimen.2 One of the reasons for the poor cure rate in this disease is the inadequacy of local control with definitive radiotherapy. Le Chevalier et al.3 observed that the 1-year local control rate was ~17% for patients with unresectable NSCLC treated to 65 Gy. A relationship has been shown between local failure and the subsequent appearance of distant metastases.4 Furthermore, there is evidence to suggest an association between improved local control and better overall survival. In the CHART trial, hyperfractionated radiotherapy resulted in improved local control and survival.5,6 A similar correlation between improved local control and survival was seen in the EORTC study comparing concurrent chemoradiation versus radiation alone for locally advanced NSCLC. Two-year local control improved from 19 to 31% with the addition of concurrent daily cisplatin. Two-year overall survival increased from 13 to 26% in the concurrent daily cisplatin arm.7 Therefore, an improvement in local control represents a principal goal in designing new strategies to treat NSCLC.
One approach to improve local control with definitive radiotherapy is to deliver escalating doses to the tumor bed. Although this approach has been used, it comes at the cost of greater, and potentially fatal, toxicity to the patient.8,9 Another approach to improve the therapeutic ratio for tumor control is through concomitant administration of a radiosensitizing drug during standard dose radiotherapy.10,11 Preclinical studies have shown that a class of protease inhibitors used to treat HIV, radiosensitize tumor cells both in vitro and in vivo.12,13 The mechanism for this radiosensitization seems to be mediated, in part, through inhibition of P-I-3 kinase.12
Nelfinavir is a selective, nonpeptidic, inhibitor that binds with high affinity to the active site of the HIV protease. The most common side effects of this drug is diarrhea occurring in ~30% of patients.14 This is controlled with over-the-counter antidiarrheals and usually is mild to moderate in nature not resulting in weight loss. Hyperglycemia and hyperlipidemia has been reported with prolonged use of all of the HIV protease inhibitors. Additionally, elevation of liver enzymes has been reported in HIV patients with hepatitis B and C infection as a result of immune reconstitution with elevation of the CD4 counts.15 The standard dosing regimen for nelfinavir is 1250 mg given twice daily. This regimen was proven to be effective in a phase III randomized trial (AG-542) comparing dosing regimens of nelfinavir in HIV patients.14 In vitro and in vivo studies confirm that AKT phosporylation by P-I-3 kinase is inhibited by nelfinavir when given at the serum concentrations that are routinely achieved with the standard HIV dosing regimen of 1250 mg twice daily.12
On the basis of these preclinical data, our group initiated a phase I trial of the HIV protease inhibitor nelfinavir with concurrent chemoradiotherapy for unresectable stage IIIA/IIIB NSCLC. The primary objective of this study was to determine the dose-limiting toxicities (DLTs) and the maximally tolerated dose of nelfinavir when administered with concurrent chemoradiotherapy. Response to therapy was assessed by positron emission tomography (PET) and computed tomography (CT).
MATERIALS AND METHODS
Patients aged 18 to 89 years with histologically proven NSCLC were enrolled onto this prospective trial. Patients had to be deemed unresectable by the thoracic oncology team at the University of Pennsylvania and planned for definitive chemoradiotherapy. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and not more than 10% unintended weight loss in the 6 months before enrollment. Patients were required to have sufficient hematologic and renal function to permit cisplatinum-based chemotherapy. Patients who had received prior thoracic radiotherapy were excluded. With long-term use of nelfinavir (≥3 years), there are reports of exacerbation of hyperglycemia in patients with type 2 diabetes.16 This trial mandates a short course (8 week) of nelfinavir, therefore patients with type 2 diabetes were not excluded. As mentioned previously, the liver enzyme elevation in patients with hepatitis B or C receiving nelfinavir is believed to be due to immune reconstitution in HIV infected individuals and not drug effect.15 Patients with history of HIV infection were excluded from this trial, however, patients with hepatitis B or C in the absence of HIV infection were not excluded. The Institutional Review Board at the University of Pennsylvania approved this study. All patients signed informed consent.
All subjects began taking daily oral nelfinavir (either 625 mg orally [PO] twice a day or 1250 mg PO twice a day) 7 to 14 days before the start of chemoradiotherapy. In preclinical studies, there was evidence of inhibition of Akt phosphorylation after 3 days of nelfinavir with no detectable phosphorylated Akt by immunoblot at the serum concentrations that are achieved with the dosing regimens that range from 625 to 1250 mg PO twice a day. Therefore, our starting dose level for this study was 625 mg PO twice a day with a top dose level of 1250 mg PO twice a day.12 A 7- to 14-day interval was chosen to ensure inhibition of Akt phosphorylation before initiation of chemoradiotherapy. Nelfinavir was continued at the prescribed dose level (either 625 mg PO twice a day or 1250 mg PO twice a day) during the complete course of concurrent chemoradiotherapy and discontinued on the last day of radiotherapy (Figure 1). All patients underwent CT-based treatment planning. All fields were treated every session. The gross tumor volume, clinical target volume, and planning target volume are defined according to ICRU 50. Elective irradiation of regional lymph nodes was allowed. All patients were treated using involved field technique to 66.6 Gy in 1.8 Gy/fraction. Normal tissue doses: the maximal spinal cord dose was limited to 45 Gy. No more than 30% of the total lung volume received greater than 20 Gy. No more than 50% of the total cardiac volume received greater than 40 Gy. To account for respiratory excursion, a four-dimensional CT was performed and an internal target volume generated. Before availability of a four-dimensional CT, patients with lower lobe tumors underwent fluoroscopy and a margin was generated based on diaphragmatic excursion. Upper lobe tumors were treated with an empiric 1.2 cm three dimensionally expanded margin to the clinical target volume to account for both set-up variance and tumor excursion.
Standard chemotherapy consisting of cisplatinum and etoposide was administered as concurrent therapy with radiation in accordance with the standard Southwest Oncology Group regimen.17,18 Cisplatinum 50 mg/m2 was administered on days 1, 8, 29, and 36, with pretreatment and posttreatment hydration and a polyantiemetic regimen. Etoposide 50 mg/m2 was administered days 1 to 5 and 29 to 33.
Toxicity and Response Assessment
DLTs were defined as any treatment-related grade 4 hematologic toxicity requiring a break in therapy for greater than 14 days or nonhematologic grade 3 or higher toxicity except esophagitis and pneumonitis. This definition of DLT was chosen as treatment breaks in chemotherapy commonly occur because of hematologic toxicity in patients receiving concurrent chemoradiotherapy for locally advanced NSCLC.19 Given the anticipated rate of grade 3 esophagitis of up to 50% and grade 3 pneumonitis of up to 30% in patients receiving concurrent chemoradiotherapy alone, these were not considered to be DLTs for nelfinavir in this trial.20 Nelfinavir dose was escalated using a standard 3 + 3 design with allowance for accrual of an additional three patients at the maximally tolerated dose. All patients underwent either a CT of the chest (12/12) and/or a PET/CT (9/12) 3 months after completion of treatment for assessment of response. All PET/CT scans were reviewed by an independent nuclear medicine physician (DP) and metabolic response was determined as previously described by Kong et al.21 All CT scans were scored by the RECIST criteria by an independent radiologist (M.A.R.). Local failure was defined as radiographic evidence of relapse within the primary tumor. Regional failure was defined as radiographic evidence of relapse within the regional hilar, mediastinal, or supraclavicular nodes. Distant failure was defined as failure in a nonregional nodal or extrathoracic site.
A total of 16 patients with biopsy proven stage IIIA or IIIB NSCLC were enrolled from June 2007 to January 2009, of which 13 received at least one dose of nelfinavir. Three patients were found to have metastatic disease and therefore ruled ineligible before initiation of nelfinavir. As stated above, all 13 patients were followed for acute toxicity and 12 patients who received nelfinavir and initiated concurrent chemoradiotherapy were assessed for response to therapy. The patient characteristics of the 12 response-evaluable patients followed for response assessment are given in Table 1. The mean age was 59 years and 58.3% were males. The majority (58.3%) of the patients had stage IIIB disease. T stage was T1/T2 in 16.6%, T3 in 50%, and T4 in 33.3%. N stage was N2 in 75% and N3 in 25%. Performance status was 80 or greater (80–90). Histology was adenocarcinoma in 42%, squamous cell in 42%, and poorly differentiated in 16%.
A total of five patients were accrued to dose level 1 (625 mg PO twice a day, dose level 1). The final two patients in the dose cohort should have been escalated to 1250 mg twice a day but were identified to have inadvertently taken the dose level 1 dose at the time of initial pill diary audit (14 days after initiation of drug). After discussion with the Abramson Cancer Center’s Clinical Trial Scientific Review and Monitoring Committee, it was decided that these two patients should continue at the lower dose level. A total of eight patients were accrued to dose level 2 (1250 mg PO twice a day; dose level 2). One patient withdrew after 2 days of nelfinavir therapy before initiation of chemoradiotherapy. This patient is followed for toxicity only. One patient discontinued because of anxiety (not drug related) after 19 days of nelfinavir (1980 cGy radiation dose). Therefore, although eight patients were accrued to dose level 2, only seven were followed for response assessment. All eight were followed for toxicity.
The toxicities associated with each dose level of nelfinavir are given in Table 2. There were no DLTs. The rate of grade 3 or 4 toxicities appeared similar for the two dose levels. Two patients initiated nelfinavir with concurrent chemoradiotherapy and then withdrew from the study: one patient withdrew as a result of anxiety (not drug related) as noted above and a second patient withdrew after 5 weeks of concurrent chemoradiotherapy with nelfinavir because of treatment-related grade 3 esophagitis. All other patients completed nelfinavir with concurrent chemoradiotherapy as per protocol, with no delays in radiotherapy.
The primary grade 3 or 4 hematologic toxicity observed was leukopenia. Three patients at dose level 1 (60%) and six patients at dose level 2 (75%) experienced grade 3 or 4 leukopenia. No patients required dose attenuation of chemotherapy or nelfinavir.
There were no nonhematologic grade 4 toxicities. The primary nonhematologic grade 3 toxicity was esophagitis experienced by three patients at dose level 2 (37.5%) and one patient at dose level 1 (20%). One patient at dose level 2 withdrew because of difficulty with pill swallowing secondary to esophagitis after 5 weeks. He was admitted with a complaint of difficulty swallowing, nausea, and fatigue (all scored as grade 3) and discontinued nelfinavir during the hospitalization. One patient at dose level 2 had grade 3 esophagitis and orthostatic hypotension requiring home IV fluids for 2 weeks after completion of chemoradiotherapy. This was felt to be attributable to chemoradiotherapy and not thought to be a nelfinavir-related toxicity. One patient at dose level 2 developed grade 3 pulmonary toxicity (dyspnea) requiring hospital admission for one night. This occurred before initiation of chemoradiotherapy while the patient was on nelfinavir. A CT of the chest was obtained to rule out pulmonary embolism. No disease progression was evident on this scan. The patient was given nebulizers overnight and discharged the following morning. Her dyspnea resolved without any further intervention.
One patient at dose level 2 developed a grade 3 deep venous thrombosis (DVT) requiring hospitalization 1 month after discontinuation of nelfinavir and withdrawal from the study as a result of anxiety. The patient was admitted and initiated on anticoagulation. The DVT was not felt to be related to study drug. This patient also experienced grade 3 fatigue 2 weeks after withdrawal from the study because of anxiety. She reported fatigue severe enough to interfere with her activities of daily living. The rate of grade 3 or 4 nonhematologic toxicities appeared to be similar between the two dose levels.
The overall rate of pill compliance on study ranged from 65 to 100% with a median pill compliance rate of 98%. Pill compliance rate appeared to be comparable for the two dose levels.
Response and Follow-Up
Table 3 shows the clinical outcome of all 12 patients followed for response. Four patients achieved a complete response (CR) and seven patients achieved a partial response (PR). Nine of the 12 patients underwent a PET/CT at 3 months after completion of therapy. Five of the nine patients experienced a metabolic CR within the radiation field (locoregional CR) and the remaining four had a PR with at least a 30% reduction in standardized uptake value (Figure 2). One patient experienced local progression at 9 months after study entry identified on a routine follow-up CT scan, which also documented distant progression. All other patients are locally controlled and alive or were locally controlled at the time of death.
Seven patients experienced distant disease progression. Five of the seven patients have died of distant disease. Two patients recurred distantly and have completed salvage therapy and are under follow-up. In one patient, a biopsy confirmed metastases in the adrenal gland and cervical lymph node. The patient was treated with salvage focal radiotherapy to both of these sites and is currently controlled 9 months after receiving salvage therapy. In another patient, a biopsy confirmed supraclavicular nodal metastasis 13 months after study entry and received concurrent chemoradiotherapy as salvage treatment. The patient was subsequently identified to have a contralateral fluorodeoxyglucose-avid pulmonary nodule, which was not amenable to biopsy 19 months after study entry. The case was reviewed in the multidisciplinary tumor board and felt to be consistent with recurrence. The patient received salvage stereotactic body radiation therapy to this contralateral nodule. He remains controlled 7 months after stereotactic body radiation therapy without any further therapy. There are four patients who are alive without evidence of disease. Two patients had only a partial response on CT and as a result both underwent biopsy. One patient had a mediastinal nodal biopsy, which was negative for malignancy and revealed lymphocytes only. The second patient underwent biopsy of a residual parenchymal lung mass that confirmed fibrosis. Eleven of twelve patients had a best response of at least a partial response with four complete responders on CT by RECIST criteria (Figure 3).
This study reports the safety and feasibility of nelfinavir administration with concurrent chemoradiotherapy in patients with unresectable locally advanced NSCLC. Activation of signal transduction pathways has been shown to be a cause of intrinsic radiation resistance with much work focusing on EGFR, Ras, and Akt. Our group has demonstrated that p-Akt is a marker for cells that are relatively resistant to radiotherapy. We have also shown that nelfinavir, a protease inhibitor used in the treatment of HIV inhibits PI3K/AKT signaling and sensitizes tumor cells to killing by ionizing radiation in vitro and in vivo.12 Interestingly, we found that the radiosensitizing effect of nelfinavir and other inhibitors that downregulate PI3K/AKT signaling is greater in vivo than would be predicted on the basis of the in vitro clonogenic survival assays.12 We therefore examined factors that might play a role in the in vivo radiation response and found that nelfinavir administration downregulates vascular endothelial growth factor signaling and improves tumor oxygenation. We, and others, have also demonstrated that nelfinavir in animal models improves tumor perfusion suggesting that the observed enhancement of tumor oxygenation is due to increased blood flow to the tumor bed22; whether this represents an important mechanism of radiosensitization is not established, but we hypothesize that it is. Clearly, favorable modulation of the tumor microenvironment is not the only mechanism of radiosensitization because of the radiosensitization observed in vitro. These observations led to our hypothesis that nelfinavir and other agents such as gefitinib inhibit critical intracellular signaling pathways and alter the tumor microenvironment leading to decreased vascular permeability and vascular normalization, improved tumor perfusion, and increased oxygenation. Therefore, unlike targeted vascular endothelial growth factor inhibitors, nelfinavir can potentially address both intrinsic and extrinsic mechanisms of radiation resistance.
On the basis of these preclinical data, we initiated a phase I clinical trial of nelfinavir with concurrent chemoradiotherapy for patients with locally advanced NSCLC. Two dose levels were tested in this study: 625 mg PO twice a day and 1250 mg PO twice a day. Both dose levels were well tolerated. Although no DLT was observed, escalation did not continue past the recommended dose of nelfinavir used in HIV therapy.
Our data suggest that nelfinavir may have activity in NSCLC. The locoregional metabolic response rate was 100% with five of nine patients (56%) having a CR on PET/CT obtained 3 months after completion of treatment. Although these results compare favorably with the 73% partial metabolic response and 23% complete metabolic response rate on PET in this population in previously published studies,21 it is important to note that the conclusions that can be drawn from the response data in our study are limited by the small patient numbers and potential for patient selection bias.
These data suggest that nelfinavir may achieve radiosensitization in NSCLC. Brunner et al.23 recently published their experience with nelfinavir and concurrent chemoradiotherapy in locally advanced pancreatic cancer with similar response rates. Of 12 patients with borderline resectable/unresectable pancreatic cancer, six were able to undergo surgical resection after chemoradiotherapy with nelfinavir. One patient had a pathologic CR to therapy. Interestingly, they also observed a higher rate of response on PET than on CT as this study. This suggests that PET may provide better discrimination of residual disease from fibrosis after radiotherapy.
There is emerging data on antineoplastic therapy in HIV patients who are being treated with HIV protease inhibitors.24 Nelfinavir is an inducer of CYP3A4 and etoposide is metabolized by this enzyme, therefore there is the potential for a drug interaction. There are conflicting data that whether this interaction would result in potential antagonism or enhancement of etoposide by nelfinavir as the CYP3A4 metabolites of etoposide have cytotoxic effect.25 At present, although data were limited, there is no evidence of enhancement of grade 4 toxicities in trials of HIV patients receiving etoposide while on nelfinavir.26,27 Therefore, the standard platform of platinum etoposide was used in this phase I trial. However, it should be noted that because of the small patient numbers in this study, it is not possible determine whether nelfinavir had either an antagonistic or enhancing effect on the actions of etoposide in our patient population.
Because there were no DLTs observed in this trial, the recommended phase II dose of nelfinavir with concurrent chemoradiotherapy was determined to be 1250 mg PO twice a day. The predominant pattern of failure was distant disease, with only one patient experiencing local progression in this study. This underscores the importance of improving systemic treatment approaches in this disease. Based on the promising response rate and local control observed in this study, we are moving forward with a phase II trial.
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Radiotherapy; Concurrent chemoradiotherapy; Locally advanced non-small cell lung cancer; Radiosensitizer
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