Photofrin Dailymed

Clinical studies of photodynamic therapy (PDT) with PHOTOFRIN were conducted in patients with obstructing esophageal and endobronchial non-small-cell lung cancers (NSCLC), in patients with early-stage radiologically occult endobronchial cancer, and in patients with high-grade dysplasia (HGD) in Barrett’s esophagus (BE). In all clinical studies, the method of PDT administration was essentially identical. A course of therapy consisted of one injection of PHOTOFRIN (2 mg/kg administered as a slow intravenous infusion over 3–5 minutes) followed by up to two non-thermal applications of 630 nm laser light. Light doses of 300 J/cm of diffuser length were used in esophageal cancer. Light doses of 200 J/cm of diffuser length were used in endobronchial cancer for both palliation of obstructing cancer and treatment of superficial lesions. Light doses of 130 J/cm of diffuser length using a centering balloon for the first application and 50 J/cm of diffuser length without a centering balloon for the second application were used for HGD in BE [see Dosage and Administration ( 2.2)] . In all cases, the first application of light occurred 40–50 hours after PHOTOFRIN.

For treatment of esophageal cancer, optional debridement of residua could be performed via endoscopy 96-120 hours after PHOTOFRIN administration, after which any residual tumor could be retreated with a second laser light application at the same light dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN were allowed after 1 month, up to a maximum of 3 courses.

For treatment of endobronchial cancer, debridement of residua was performed via bronchoscopy 96-120 hours after PHOTOFRIN administration, after which any residual tumor could be retreated with a second laser light application at the same light dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN were allowed after 1 month, up to a maximum of 3 courses.

For ablation of HGD in BE, a second laser light application of 50 J/cm of diffuser length without a centering balloon could be given 96-120 hours after PHOTOFRIN administration for untreated areas (“skip” areas). Additional courses of PDT with PHOTOFRIN were allowed after 3 months, up to a maximum of 3 courses.

14.1 Esophageal Cancer

PDT with PHOTOFRIN was utilized in a multicenter, single-arm study in 17 patients with completely obstructing esophageal carcinoma. Assessments were made at 1 week and 1 month after the last treatment procedure. As shown in Table 10 , after a single course of therapy, 94% of patients obtained an objective tumor response and 76% of patients experienced some palliation of their dysphagia. On average, before treatment these patients had difficulty swallowing liquids, even saliva. After one course of therapy, there was a statistically significant improvement in mean dysphagia grade (1.5 units, p <0.05) and 13 of 17 patients could swallow liquids without difficulty 1 week and/or 1 month after treatment. Based on all courses, three patients achieved a complete tumor response (CR). In two of these patients, the CR was documented only at Week 1 as they had no further assessments. The third patient achieved a CR after a second course of therapy, which was supported by negative histopathology and maintained for the entire follow-up of 6 months.

Of the 17 treated patients, 11 (65%) received clinically important benefit from PDT. Clinically important benefit was defined hierarchically as a complete tumor response (3 patients), achievement of normal swallowing (2 patients went from Grade 5 dysphagia to Grade 1), or achievement of a marked improvement of two or more grades of dysphagia with minimal adverse reactions (6 patients). The median duration of benefit in these patients was 69 days. Duration of benefit was calculated only for the period with documented evidence of improvement. All of these patients were still in response at their last assessment and, therefore, the estimate of 69 days is conservative. The median survival for these 11 patients was 115 days.

14.2 Endobronchial Cancer

Two randomized multicenter studies were conducted to compare the safety and efficacy of PHOTOFRIN PDT versus Nd:YAG laser therapy for reduction of obstruction and palliation of symptomatic patients with partially or completely obstructing endobronchial non-small-cell lung cancer. Assessments were made at 1 week and at monthly intervals after treatment. Table 11 shows the results from all randomized patients in the two studies combined. Objective tumor response rates (CR + PR), which demonstrate reduction of obstruction, were 59% for PDT and 58% for Nd:YAG at Week 1. The response rate at 1 month or later was 60% for PDT and 41% for Nd:YAG.

Patient symptoms were evaluated using a 5- or 6-grade pulmonary symptom severity rating scale for dyspnea, cough, and hemoptysis. Patients with moderate to severe symptoms are those most in need of palliation. Improvements of 2 or more grades are considered to be clinically significant. Table 12 shows the percentages of patients with moderate to severe symptoms at baseline who demonstrated a 2-grade improvement at any time during the interval evaluated.

TABLE 10. Course 1 Efficacy Results in Patients with Completely Obstructing Esophageal Cancer

EFFICACY PARAMETER	PDT N=17
OBJECTIVE TUMOR RESPONSE CR+PR, CR = complete response (absence of endoscopically visible tumor), PR = partial response (appearance of a visible lumen). (% of patients)
Week 1	82%
Month 1	35% Eight of the 17 treated patients did not have assessments at Month 1.
Any assessment Week 1 or Month 1.	94%
IMPROVEMENT Patients with at least a one-grade improvement in dysphagia grade. IN DYSPHAGIA (% of patients)
Week 1	71%
Month 1	47%
Any assessment	76%
MEAN DYSPHAGIA GRADE Dysphagia Scale: Grade 1 = normal swallowing; Grade 2 = difficulty swallowing some hard solids, can swallow semisolids; Grade 3 = unable to swallow any solids, can swallow liquids; Grade 4 = difficulty swallowing liquids; Grade 5 = unable to swallow saliva. AT BASELINE (units)	4.6
MEAN IMPROVEMENT ¶ IN DYSPHAGIA GRADE (units)
Week 1	1.4
Month 1	1.5
MEAN NUMBER OF LASER APPLICATIONS (units)	1.4

TABLE 11. Efficacy Results from Studies in Late-Stage Obstructing Endobronchial Cancer All Randomized Patients Statistical comparisons were precluded by the amount of missing data at Month 1 or later (e.g., for tumor response, PDT 28% missing, Nd:YAG 38%).

EFFICACY PARAMETER	PDT N=102	Nd:YAG N=109
OBJECTIVE TUMOR RESPONSE CR+PR where CR = complete response (absence of bronchoscopically visible tumor) and PR = partial response (increase of 50% in the smallest luminal diameter; or any appearance of a lumen for completely obstructing tumors).
Week 1	59%	58%
Month 1 or later	60%	41%a
ATELECASIS IMPROVEMENT In patients with atelectasis at baseline.	n=60	N=71
Week 1	35%	18%
Month 1 or later	35%	20%

TABLE 12. Efficacy Results from Studies in Late-stage Obstructing Endobronchial Cancer Clinically Significant Improvements in Patients with Moderate to Severe Symptoms at Baseline Statistical comparisons were precluded by the amount of missing data at Month 1 or later.

CLINICALLY SIGNIFICANT    SYMPTOM IMPROVEMENT Dyspnea was graded on a 6-point severity rating scale; cough and hemoptysis on a 5-point scale. Clinically significant improvement was defined as a change of at least two grades from baseline.	PDT N=102	Nd:YAG, N=109
ANY SYMPTOM	n=89	n=89
Week 1	25%	29%
Month 1 or later	40%	27%a
DYSPNEA	n=60	n=68
Week 1	15%	18%
Month 1 or later	23%	13%
COUGH	n=63	n=65
Week 1	6%	9%
Month 1 or later	24%	8%
HEMOPTYSIS	n=24	n=31
Week 1	58%	29%
Month 1 or later	79%	35%

In a separate retrospective analysis, patients were individually evaluated to identify those patients whose benefit to risk ratio was most favorable, i.e., those who obtained clinically important benefit with minimal adverse reactions. Clinically important benefit was defined as one of the following:

• A substantial improvement in pulmonary symptoms at Month 1 or later (dyspnea 2 grades, hemoptysis 3 grades, cough 3 grades or increase in FEV1 40%);
• A moderate improvement in symptoms at Month 2 or later (dyspnea 1 grade, cough 2 grades, hemoptysis 2 grades or increase in FEV1 20%); or
• A durable objective tumor response (CR or PR maintained to Month 2 or longer).

Thirty-six (36) of the 99 PDT-treated patients (36%) and 23 of the 99 Nd:YAG-treated patients (23%) received clinically important benefit with only minimal or moderate toxicities of short duration. Thirty-four (34) of 99 PDT- treated patients demonstrated improvements in 2 or more efficacy endpoints (dyspnea, cough, hemoptysis, sputum, atelectasis, pulmonary function tests of FEV1 or FVC, Karnofsky Performance Score or tumor response) and 29 patients had improvements in 3 or more.

The median duration of documented benefit in the 36 patients was 63 days. In these patients with late-stage obstructing lung cancer, median survival was 174 days in PDT-treated patients and 161 days in Nd:YAG- treated patients.

The efficacy of PHOTOFRIN PDT was also evaluated in the treatment of microinvasive endobronchial tumors in 62 inoperable patients in three noncomparative studies. Microinvasive lung cancer is defined histologically as disease, which invades beyond the basement membrane but not through or into the cartilage. For 11 of the 62 patients, it was clearly documented that surgery and radiotherapy were not indicated. These 11 patients were all inoperable for medical or technical reasons. Radiotherapy was not indicated due to prior highdose radiotherapy (7 patients), poor pulmonary function (2 patients), multifocal multilobar disease (1 patient), and poor medical condition (1 patient). As shown in Table 13 , the complete tumor response rate, biopsy-proven at least 3 months after treatment, was 50%, median time to tumor recurrence was more than 2.7 years, median survival was 2.9 years and disease-specific survival was 4.1 years.

TABLE 13. Overall Efficacy in Patients with Superficial Endobronchial Tumor

EFFICACY PARAMETER	PDT
	n=11	n=62
COMPLETE TUMOR RESPONSE, BIOPSY-PROVEN AT 3 MONTHS
Number of Patients (%)	3 (27)	31 (50) Not included are an additional 18 patients (6 patients not eligible for surgery or radiotherapy) who had complete tumor responses which were documented earlier than 3 months after treatment.
TIME TO TUMOR RECURRENCE IN PATIENTS WITH COMPLETE RESPONSE
Number of Patients (%) with Recurrences	1(33)	11(35)
Median Time to Tumor Recurrence		>2.7 years
[95% Confidence Interval]		[1.6, The upper limit of the confidence interval could not be estimated due to an insufficient number of patients whose tumors recurred (Time to Tumor Recurrence) or who died (Survival).]
SURVIVAL
Number of Patients (%) who Died of Any Cause	4 (36)	32 (52)
Median Survival		2.9 years
[95% Confidence Interval]		[2.1, 5.7]
DISEASE-SPECIFIC SURVIVAL
Number of Patients (%) who Died of Lung Cancer	3 (27)	22 (35)
Median Disease-Specific Survival		4.1 years
[95% Confidence Interval]		[2.5, †]

14.3 High-Grade Dysplasia in Barretts Esophagus

The safety and efficacy of PDT with PHOTOFRIN in ablation of HGD in patients with BE was assessed in one controlled randomized clinical study and two supportive studies.

Controlled Randomized Study

A multicenter, pathology blinded, randomized, controlled study was conducted in North America and Europe to assess the efficacy of PDT with PHOTOFRIN plus omeprazole (PHOTOFRIN PDT + OM) in producing complete ablation of HGD in patients with BE compared to control patients receiving omeprazole alone (OM Only). A total of 485 patients with the diagnosis of HGD were screened for the study; 208 (43%) were randomized to treatment, 237 (49%) were excluded because the diagnosis of HGD was not confirmed and 40 (8%) did not meet other screening criteria or declined to participate in the study.

The high patient exclusion rate re-enforces the recommendation by the American College of Gastroenterology that the diagnosis of HGD in BE should be confirmed by an expert gastrointestinal pathologist. Patients were centrally randomized in a 2:1 proportion to receive PHOTOFRIN PDT + OM (138 patients) or OM Only (70 patients). All patients underwent rigorous systematic quarterly endoscopic biopsy surveillance. Four-quadrant jumbo biopsies at every 2 cm of the entire Barretts mucosa were obtained at each follow-up visit (every three months or six months if four consecutive quarterly follow-up endoscopic biopsy results were negative for HGD). All histological assessments were carried out at a central pathology laboratory and read by pathologists blinded to the treatment administered.

A total of 208 patients who had biopsy-proven HGD in BE were enrolled in the initial 2-year phase of the study. Of those, 199 patients were considered evaluable: 130 of 138 (94%) patients randomized to the PHOTOFRIN PDT + OM group and 69 of 70 (99%) randomized to the OM Only group had no esophageal invasive cancer, suspicion of esophageal invasive cancer, lymph node involvement, or metastases, and had received at least one PHOTOFRIN PDT course or one week of OM treatment, respectively. A disproportionate percentage of patients were discontinued from the OM Only group during the initial 2-year phase leaving 81 (59%) patients in the PHOTOFRIN PDT + OM group and 21 (30%) patients in the OM Only group at the end of the 2-year phase. Consequently, a total of 102 patients who completed the initial 2-year phase were eligible for continuation into the long-term phase until completion of 5 years; of those, 48 (59%) patients from the PHOTOFRIN PDT + OM group and 13 (62%) patients from the OM Only group consented to pursue the long- term phase until completion of 5 years. The mean age was 66 years (38 to 89 years) in the PHOTOFRIN PDT + OM group, and 67 (36 to 88 years) in the OM Only group. The patients in both treatment groups were predominantly male (85%), Caucasian (99%), and former smokers (64%). These characteristics are typical of patients with HGD in BE. Patients randomized to the PHOTOFRIN PDT + OM treatment received up to three courses of treatment separated by at least 90 days. Each course consisted of intravenous administration of 2.0 mg/kg of PHOTOFRIN followed 40-50 hours later by a 630 nm laser light dose of 130 J/cm of diffuser length delivered using a centering balloon. A second laser light dose of 50 J/cm of diffuser length could be administered without a centering balloon 96-120 hours after the injection of PHOTOFRIN for treatment of skip areas. Since centering balloons are up to 7 cm in length, patients with more extensive HGD were treated with two or three courses. Both the PHOTOFRIN PDT treatment group and the control group received 20 mg of omeprazole BID to decrease reflux esophagitis. The mean duration of the follow-up period was 34 months (0- 67 months) for the PHOTOFRIN PDT + OM group and 25 months (0-65 months) for the OM Only group.

The major efficacy outcome measure was the Complete Response rate (CR3 or better) at any one of the endoscopic assessment time points. The CR3 or better response was defined as the complete ablation of HGD and referred to as a composite of the following three response levels.

• CR1 Complete replacement of all Barretts metaplasia and dysplasia with normal squamous cell epithelium;
• CR2 Ablation of all histological grades of dysplasia, including patients with indefinite grade of dysplasia, but some areas of Barretts epithelium still remain; and
• CR3 Ablation of all HGD but with some areas of low-grade dysplasia with or without areas which are indefinite for dysplasia, or areas of Barretts metaplastic epithelium.

Additional efficacy endpoints included:

• Quality of Complete Response, which consisted of CR1 and CR2 or better.
• Duration of CR;
• Time to Progression to Cancer.

Table 14 presents the overall clinical response for both treatment groups in the intent-to-treat (ITT) population whose response was CR3 or better at any one of the evaluation time points. Overall, PHOTOFRIN PDT + OM was effective in eliminating HGD in patients with BE. The proportion of responders was significantly higher in the PHOTOFRIN PDT + OM group than in the OM Only group (77% vs. 39%, respectively; p<0.0001).

The quality of response in the PHOTOFRIN PDT + OM group was significantly better than that measured in the OM Only group at all response levels (p<0.0001). Seventy-two (52%) patients in the PHOTOFRIN PDT + OM group achieved a CR1 response as compared to only five (7%) patients in the OM Only group. Eighty-one (59%) patients in the PHOTOFRIN PDT + OM group achieved a CR2 or better response as compared to ten (14%) patients in the OM Only group.

TABLE 14. Complete Response Rates After a Minimum Follow-Up of 24 Months in the ITT Population

NOTE: Six patients in the PHOTOFRIN PDT + OM group and three patients in the OM Only group without post-baseline biopsy data are considered as non-responders.
Responders	TREATMENT GROUPS
	PHOTOFRIN PDT+OM N=138	OM Only N=70	p-value Fishers Exact test.
CR3 or better CR3 or better: Ablation of all areas of HGD.	n = 106	n= 27
Proportion (%) 95% CI	0.768 (76.8)	0.386 (38.6)	<0.0001
	(0.689, 0.836)	(0.272, 0.510)

At the end of the long-term phase, the median response duration was 44.6 months (95% CI: 15.0-not reached, months) in the PHOTOFRIN PDT + OM group compared to 3.2 months (95% CI: 3.0- 3.4, months) in the OM Only group.

At the end of the initial 2 year phase, the time to progression to cancer was significantly longer in the PHOTOFRIN PDT + OM group compared to the OM Only group (HR=0.36 (95% CI: 0.19-0.69), a hazard ratio less than 1 favors the PHOTOFRIN PDT + OM group). The proportion of patients progression to cancer was lower in the PHOTOFRIN PDT + OM group than in the OM Only group: 13% (18 of 138 patients) vs. 28% (20 of 70 patients).

Complete response was influenced by the following factors: treatment with PHOTOFRIN PDT + OM (vs. OM Only), single focus of HGD (vs. multiple foci), and prior omeprazole intake of at least 3 months (yes vs. no). Complete response was not influenced by the duration of HGD, length of BE, nodular conditions, gender, age, smoking history, and study centers size.

Supportive Studies

Two uncontrolled, supportive studies were conducted that were physician-sponsored, single center Phase II trials. Both studies included patients that had low-grade dysplasia (LGD), HGD and early adenocarcinoma. All HGD in BE patients were treated with PHOTOFRIN PDT and omeprazole.

The first study enrolled 99 patients (44 with HGD); the purpose of this study was to determine the required light dose to produce effective results. The second study enrolled 86 patients (42 with HGD), who were randomized to receive either PHOTOFRIN PDT with prednisone or PHOTOFRIN PDT without prednisone to determine whether steroid treatment would reduce the incidence and severity of esophageal strictures.

A CR3 or better response was demonstrated in 93% of 44 patients with HGD in the first study and in 95% of 42 patients with HGD in the second study after a minimum follow-up of 12 months. A CR2 or better response was achieved in 82% of patients in the first study and in 91% of patients in the second study. A CR1 response occurred in 57% of patients in the first study and in 60% of the second study. Progression to cancer during the above follow-up period occurred in 18% of patients in the first study and in 7% of patients in the second study. No reduction in the incidence or severity of esophageal strictures was found in the prednisone group in the second study.