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PHOTOFRIN(porfimer sodium for Injection)

2016-12-04 09:28:49 来源: 作者: 【大中小】浏览:357次评论:0条

Description

PHOTOFRIN® (porfimer sodium) for Injection is a photosensitizing agent used in the photodynamic therapy (PDT) of tumors and of high-grade dysplasia (HGD) in Barrett’s esophagus (BE). Following reconstitution of the freeze-dried product with 5% Dextrose Injection (USP) or 0.9% Sodium Chloride Injection (USP), it is injected intravenously. This is followed 40−50 hours later by illumination of the tumor or HGD in BE with laser light (630 nm wavelength). PHOTOFRIN® is not a single chemical entity; it is a mixture of oligomers formed by ether and ester linkages of up to eight porphyrin units. It is a dark red to reddish brown cake or powder. Each vial of PHOTOFRIN® contains 75 mg of porfimer sodium as a sterile freeze-dried cake or powder. Hydrochloric Acid and/or Sodium Hydroxide may be added during manufacture to adjust the pH to within 7.2-7.9. There are no preservatives or other additives. The structural formula below is representative of the components present in PHOTOFRIN®.

Clinical Pharmacology

Pharmacology

The cytotoxic and antitumor actions of PHOTOFRIN® are light and oxygen dependent. Photodynamic therapy with PHOTOFRIN® is a two-stage process. The first stage is the intravenous injection of PHOTOFRIN®. Clearance from a variety of tissues occurs over 40-72 hours, but tumors, skin, and organs of the reticuloendothelial system (including liver and spleen) retain PHOTOFRIN® for a longer period. Illumination with 630 nm wavelength laser light constitutes the second stage of therapy. Tumor selectivity in treatment occurs through a combination of selective retention of PHOTOFRIN® and selective delivery of light. Cellular damage caused by PHOTOFRIN® PDT is a consequence of the propagation of radical reactions. Radical initiation may occur after PHOTOFRIN® absorbs light to form a porphyrin excited state. Spin transfer from PHOTOFRIN® to molecular oxygen may then generate singlet oxygen. Subsequent radical reactions can form superoxide and hydroxyl radicals. Tumor death also occurs through ischemic necrosis secondary to vascular occlusion that appears to be partly mediated by thromboxane A2 release. The laser treatment induces a photochemical, not a thermal, effect. The necrotic reaction and associated inflammatory responses may evolve over several days.

Pharmacokinetics

Following a 2 mg/kg dose of porfimer sodium to 4 male cancer patients, the average peak plasma concentration was 15 ± 3 mcg/mL, the elimination half-life was 250 ± 285 hours, the steady-state volume of distribution was 0.49 ± 0.28 L/kg, and the total plasma clearance was 0.051 ± 0.035 mL/min/kg. The mean plasma concentration at 48 hours was 2.6 ± 0.4 mcg/mL. The influence of impaired hepatic function on PHOTOFRIN® disposition has not been eva luated.

PHOTOFRIN® was approximately 90% protein bound in human serum, studied in vitro. The binding was independent of concentration over the concentration range of 20−100 mcg/mL.

The pharmacokinetics of PHOTOFRIN® was also studied in 24 healthy subjects (12 men and 12 women) who received a single dose of 2 mg/kg PHOTOFRIN® given via the intravenous route. The serum decay was bi-exponential, with a slow distribution phase and a very long elimination phase. The elimination half-life was 415 ± 104 hours (17 ± 4.3 days). The Cmax was determined to be 40 ± 11.6 mcg/mL and AUCinf was 2400 ± 552 mcg•hour/mL. Women had a lower Cmax and a higher AUC. The clinical significance of these differences is unknown. The Tmax was approximately 1.5 hours in women and 0.17 hours in men. At the time of intended photoactivation 40-50 hours after injection, the pharmacokinetic profiles of PHOTOFRIN® in men and women were similar.

Clinical Studies

Clinical studies of PDT with PHOTOFRIN® were conducted in patients with obstructing esophageal and endobronchial non-small-cell lung cancers, in patients with early-stage radiologically occult endobronchial cancer, and in patients with high-grade dysplasia (HGD) associated with 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 injection over 3−5 minutes) followed by up to two non-thermal applications of 630 nm laser light. Light doses of 300 Joules/cm (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. For the ablation of HGD in BE, the light dose administered was 130 J/cm of diffuser length using a centering balloon (for details, see DOSAGE AND ADMINISTRATION). In all cases, the first application of light occurred 40−50 hours after PHOTOFRIN® injection.

For treatment of esophageal and endobronchial cancer, debridement of residua was performed via endoscopy/bronchoscopy 96−120 hours after injection, after which any residual tumor could be retreated with a second laser light application at the same dose used for the initial treatment. Additional courses of PDT with PHOTOFRIN® were allowed after 1 month, up to a maximum of three 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 the PHOTOFRIN® injection for untreated areas ( "skip" areas). Additional courses of PDT with PHOTOFRIN® were allowed after 3 months, up to a maximum of three courses.

Esophageal Cancer

Photodynamic therapy 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 1, 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.

TABLE 1. Course 1 Efficacy Results in Patients with Completely Obstructing Esophageal Cancer
* CR+PR, CR = complete response (absence of endoscopically visible tumor), PR = partial response (appearance of a visible lumen). † Eight of the 17 treated patients did not have assessments at Month 1. ‡ Week 1 or Month 1. § Patients with at least a one-grade improvement in 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.
EFFICACY PARAMETER	PDT N=17

OBJECTIVE TUMOR RESPONSE * (% of patients)
Week 1	82%
Month 1	35%†
Any assessment‡	94%

IMPROVEMENT § IN DYSPHAGIA (% of patients)
Week 1	71%
Month 1	47%
Any assessment ‡	76%

MEAN DYSPHAGIA GRADE ¶ 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

Endobronchial Cancer

Two randomized multicenter Phase III 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 2 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.

TABLE 2. 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%) . † CR+PR, CR = complete response (absence of bronchoscopically visible tumor), PR = partial response (increase of ≥50% in the smallest luminal diameter); for completely obstructing tumors, any appearance of a lumen). ‡ In patients with atelectasis at baseline.
EFFICACY PARAMETER	PDT N=102 (% of Patients)	Nd:YAG N=109 (% of Patients)
OBJECTIVE TUMOR RESPONSE †
Week 1	59%	58%
Month 1 or later	60%	41% *
ATELECTASIS IMPROVEMENT‡	n=60	n=71
Week 1	35%	18%
Month 1 or later	35%	20%

Patient symptoms were eva luated 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 3 shows the percentages of patients with moderate to severe symptoms at baseline who demonstrated a 2-grade improvement at any time during the interval eva luated.

TABLE 3. 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. † 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.
CLINICALLY SIGNIFICANT SYMPTOM IMPROVEMENT †	PDT N=102 (% of Patients)	Nd:YAG N=109 (% of Patients)
ANY SYMPTOM	n=89	n=89
Week 1	25%	29%
Month 1 or later	40%	27%*
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 eva luated 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 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 eva luated 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 high-dose radiotherapy (7 patients), poor pulmonary function (2 patients), multifocal multilobar disease (1 patient), and poor medical condition (1 patient). As shown in Table 4, 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 4. Overall Efficacy Results in Patients with Superficial Endobronchial Tumors
* 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. † 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).
	PDT
EFFICACY PARAMETER	n=11	n=62
COMPLETE TUMOR RESPONSE, BIOPSY-PROVEN AT 3 MONTHS
Number of Patients (%)	3 (27)	31 (50)*
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,—†]
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, —†]

High-Grade Dysplasia in Barrett’s Esophagus

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

Controlled Study

A multicenter, partially blinded, randomized, controlled study was conducted in North America and Europe to assess the efficacy of PDT with PHOTOFRIN® for Injection 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 toparticipate 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 GI 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 Barrett’s 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 study. Of those, 199 patients were considered eva luable: 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. The mean age was 66 years (38 to 89 years) in the PHOTOFRIN® PDT + OM group, and 67 (36 to 88) 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. 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 primary efficacy endpoint 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 Barrett’s 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 Barrett’s epithelium still remain; and
CR3 − Ablation of all areas of HGD but with some areas of low-grade dysplasia with or without areas which are indefinite for dysplasia, or areas of Barrett’s metaplastic epithelium.

There were five secondary efficacy endpoints:

Quality of Complete Response, which consisted of two parameters:
- CR1 response (complete replacement of all Barrett’s metaplasia and dysplasia with normal squamous cell epithelium); and
- CR2 or better response (a composite endpoint of complete ablation of all grades of dysplasia and of CR1 response as defined above);
Duration of CR;
Time to Progression to Cancer;
Time to Treatment Failure (a composite endpoint of progression to cancer and other therapeutic intervention for HGD); and
Survival time

Table 5 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 eva luation 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% versus 39%, respectively; p < 0.0001).

Table 5. Complete Response Rates After a Minimum Follow-Up of 24 Months in the ITT Population
* Fisher’s Exact test. † CR3 or better: Ablation of all areas of HGD. 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.
		Treatment Groups
Responders		PHOTOFRIN ® PDT + OM	OM Only	p-value*
Numbers of patients	N	138	70
CR3 or better†	n	106	27
	Proportion (%)	0.768 (76.8)	0.386 (38.6)	< 0.0001
	95% CI	(0.689, 0.836)	(0.272, 0.510)

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. The probability of maintaining a complete response (CR3 or better) by the end of the follow-up period was 53% in PHOTOFRIN® PDT + OM group and only 13% in OM Only group.

The time to patients’ progression to cancer was significantly longer in the PHOTOFRIN® PDT + OM group than in OM Only group (see Kaplan-Meier plot below).

Figure 1. Comparison by Treatment Group of the Time to Progression to Cancer Over Time (ITT population)

At the end of the follow-up, patients in the PHOTOFRIN® PDT + OM group had an 83% chance of being cancer-free compared to 53% chance among patients in the OM Only group (p=0.0014). Durability of cancer risk reduction beyond two years has not been demonstrated.

At the end of the follow-up, the proportion of patients’ progression to cancer was statistically lower in the PHOTOFRIN® PDT + OM group than in the OM Only group: 13% (18 of 138 patients) versus 28% (20 of 70 patients), p=0.0060. Progression to cancer was related to complete response status. Patients who did not have a complete response had a greater risk of progression to cancer than patients who achieved a CR3 or better response, both in the PHOTOFRIN® PDT + OM group (38% vs. 6%) and in the OM Only group (44% vs. 4%). Patients who progressed to cancer after a complete response had mostly a CR3 response. No CR1 patients had progressed to cancer during the follow-up period.

Eighteen (13%) patients in the PHOTOFRIN® PDT + OM group and 22 (31%) patients in the OM Only group had another therapeutic intervention for HGD. Patients who experienced a progression of HGD to cancer, or who underwent therapy for HGD other than specified in the treatment arm were discontinued from the study. A disproportionate percentage of patients were discontinued from the OM Only group during the course of the study. By the end of the follow-up period, 81 (59%) patients in the PHOTOFRIN® PDT + OM group and 28 (40%) patients in the OM Only group remained in their respective treatment arms.

Median survival time could not be estimated for either group, because very few (3) patients died during the study period.

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 center’s 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.

INDICATIONS AND USAGE

Photodynamic therapy with PHOTOFRIN® is indicated for:

Palliation of patients with completely obstructing esophageal cancer, or of patients with partially obstructing esophageal cancer who, in the opinion of their physician, cannot be satisfactorily treated with Nd:YAG laser therapy.
Reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial non-small-cell lung cancer (NSCLC).
Treatment of microinvasive endobronchial NSCLC in patients for whom surgery and radiotherapy are not indicated.
Ablation of high-grade dysplasia in Barrett’s esophagus patients who do not undergo esophagectomy.

CONTRAINDICATIONS

PHOTOFRIN® is contraindicated in patients with porphyria or in patients with known allergies to porphyrins.

Photodynamic therapy is contraindicate