Romidepsin Injection

Name: Romidepsin Injection

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been performed with romidepsin. Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively). These doses were up to 1.3-fold the recommended human dose, based on body surface area.

Based on nonclinical findings, male and female fertility may be compromised by treatment with romidepsin. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-∞ values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-∞ values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

Clinical Studies

Cutaneous T-Cell Lymphoma

Romidepsin was evaluated in 2 multicenter, single-arm clinical studies in patients with CTCL. Overall, 167 patients with CTCL were treated in the US, Europe, and Australia. Study 1 included 96 patients with confirmed CTCL after failure of at least 1 prior systemic therapy. Study 2 included 71 patients with a primary diagnosis of CTCL who received at least 2 prior skin directed therapies or one or more systemic therapies. Patients were treated with romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days.

In both studies, patients could be treated until disease progression at the discretion of the investigator and local regulators. Objective disease response was evaluated according to a composite endpoint that included assessments of skin involvement, lymph node and visceral involvement, and abnormal circulating T-cells ("Sézary cells").

The primary efficacy endpoint for both studies was overall objective disease response rate (ORR) based on the investigator assessments, and defined as the proportion of patients with confirmed complete response (CR) or partial response (PR). CR was defined as no evidence of disease and PR as ≥ 50% improvement in disease. Secondary endpoints in both studies included duration of response and time to response.

Baseline Patient Characteristics

Demographic and disease characteristics of the patients in Study 1 and Study 2 are provided in Table 3.

Table 3. Baseline Patient Characteristics
(CTCL Population)
Characteristic Study 1
(N=96)
Study 2
(N=71)
Age
  N 96 71
  Mean (SD) 57 (12) 56 (13)
  Median (Range) 57 (21, 89) 57 (28, 84)
Sex, n (%)
  Men 59 (61) 48 (68)
  Women 37 (39) 23 (32)
Race, n (%)
  White 90 (94) 55 (77)
  Black 5 ( 5) 15 (21)
  Other/Not Reported 1 ( 1) 1 ( 1)
Stage of Disease at Study Entry, n (%)
  IA 0 ( 0) 1 ( 1)
  IB 15 (16) 6 ( 9)
  IIA 13 (14) 2 ( 3)
  IIB 21 (22) 14 (20)
  III 23 (24) 9 (13)
  IVA 24 (25) 27 (38)
  IVB 0 ( 0) 12 (17)
Number of Prior Skin-Directed Therapies
  Median (Range) 2 (0,6) 1 (0,3)
Number of Prior Systemic Therapies
  Median (Range) 2 (1, 8) 2 (0, 7)

Clinical Results

Efficacy outcomes for CTCL patients are provided in Table 4. Median time to first response was 2 months (range 1 to 6) in both studies. Median time to CR was 4 months in Study 1 and 6 months in Study 2 (range 2 to 9).

Table 4. Clinical Results for CTCL Patients
Response Rate Study 1
(N=96)
Study 2
(N=71)
ORR (CR + PR), n (%)
[95% Confidence Interval]
33 (34)
[25, 45]
25 (35)
[25, 49]
            CR, n (%)
            [95% Confidence Interval]
6 (6)
[2, 13]
4 (6)
[2, 14]
            PR, n (%)
            [95% Confidence Interval]
27 (28)
[19, 38]
21 (30)
[20, 43]
Duration of Response (months)
            N 33 25
            Median (range) 15 (1, 20*) 11 (1, 66*)
    *denotes censored value

Peripheral T-Cell Lymphoma

Romidepsin was evaluated in a multicenter, single-arm, international clinical study in patients with PTCL who had failed at least 1 prior systemic therapy (Study 3). Patients in US, Europe, and Australia were treated with romidepsin at a dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Of the 131 patients treated, 130 patients had histological confirmation by independent central review and were evaluable for efficacy (HC Population). Six cycles of treatment were planned; patients who developed progressive disease (PD), significant toxicity, or who met another criterion for study termination were to discontinue treatment. Responding patients had the option of continuing treatment beyond 6 cycles at the discretion of the patient and Investigator until study withdrawal criteria were met.

Primary assessment of efficacy was based on rate of complete response (CR + CRu) as determined by an Independent Review Committee (IRC) using the International Workshop Response Criteria (IWC). Secondary measures of efficacy included IRC assessment of duration of response and objective disease response (ORR, CR + CRu + PR).

Baseline Patient Characteristics

Demographic and disease characteristics of the PTCL patients are provided in Table 5.

*Stage of disease was reported at time of diagnosis for Study 3 and at time of study entry for Study 4.
Table 5. Baseline Patient Characteristics
(PTCL Population)
Characteristic Study 3
(N=130)
Study 4
(N=47)
Age (years), n 130 47
  Mean (SD) 59 (13) 59 (13)
  Median 61 59
Sex, n (%)
  Male 88 (68) 25 (53)
  Female 42 (32) 22 (47)
Race, n (%)
  White 116 (89) 40 (85)
  Black 7 (5) 4 (9)
  Asian 3 (2) 3 (6)
  Other 4 (3) 0
PTCL Subtype Based on Central Diagnosis, n (%)
  PTCL Unspecified (NOS) 69 (53) 28 (60)
  Angioimmunoblastic T-cell lymphoma (AITL) 27 (21) 7 (15)
  ALK-1 negative anaplastic large cell lymphoma (ALCL) 21 (16) 5 (11)
  Other 13 (10) 7 (16)
Stage of Disease, n (%)*
  I/II 39 (30) 2 (4)
  III/IV 91 (70) 45 (96)
ECOG Performance Status, n (%)
  0 46 (35) 20 (43)
  1 67 (51) 22 (47)
  2 17 (13) 4 (9)
Number of Prior Systemic Therapies
  Median (Range) 2 (1, 8) 3 (1, 6)

All patients in both studies had received prior systemic therapy for PTCL. In Study 4, a greater percentage of patients had extensive prior radiation and chemotherapy. Twenty-one patients (16%) in Study 3 and 18 patients (38%) in Study 4 had received prior autologous stem cell transplant and 31 (24%) and 19 (40%) patients, respectively, had received prior radiation therapy.

Clinical Results

Efficacy outcomes for PTCL patients as determined by the IRC are provided in Table 6 for Study 3. The complete response rate was 15% and overall response rate was 26%. Similar complete response rates were observed by the IRC across the 3 major PTCL subtypes (NOS, AITL, and ALK-1 negative ALCL). Median time to objective response was 1.8 months (~2 cycles) for the 34 patients who achieved CR, CRu, or PR and median time to CR was 3.5 months (~4 cycles) for the 20 patients with complete response. The responses in 12 of the 20 patients achieving CR and CRu were known to exceed 11.6 months; the follow-up on the remaining 8 patients was discontinued prior to 8.5 months.

Table 6. Clinical Results for PTCL Patients
Response Rate Study 3
(N=130)
1 Primary Endpoint.
2 Secondary Endpoint.
3 Two-sided 95% Confidence Interval.
CR+CRu, n (%)1 20 (15.4) [9.7, 22.8]3
PR, n (%)2 14 (10.8) [6.0, 17.4]3
ORR (CR+CRu+PR), n (%)2 34 (26.2) [18.8, 34.6]3

In a second single-arm clinical study in patients with PTCL who had failed prior therapy (Study 4), patients were treated with romidepsin at a starting dose of 14 mg/m2 infused over 4 hours on days 1, 8, and 15 every 28 days. Patients could be treated until disease progression at the discretion of the patient and the Investigator. The percentage of patients achieving CR + CRu in Study 4 was similar to that in Study 3.

References

“OSHA Hazardous Drugs.” OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html

How Supplied/Storage and Handling

How Supplied

Romidepsin is supplied as a kit including a sterile, lyophilized powder in a 10 mg single-dose vial containing 11 mg of romidepsin and 22 mg of the bulking agent, povidone, USP. In addition, each kit includes a single-dose sterile diluent vial containing 2.4 mL (2.2 mL deliverable volume) of 80% propylene glycol, USP, and 20% dehydrated alcohol, USP.

NDC 0069-0983-01: Romidepsin Kit containing 1 vial of romidepsin and 1 vial of diluent for romidepsin per carton.

Storage

Romidepsin for Injection is supplied as a kit containing 2 vials in a single carton. The carton must be stored at 20° to 25°C, excursions permitted between 15° to 30°C. (See USP Controlled Room Temperature.)

Procedures for proper handling and disposal of anticancer drugs should be considered. A guideline on this subject has been published [see References (15)].

(web3)