Comparision of two Temozolomide 250 mg capsules in the patient of Glioblastoma Multiforme or Anaplastic Astrocytoma patients under fasting condition.

Completed

• Conditions: Malignant neoplasm of brain, unspecified,

• Registration Number: CTRI/2012/03/002499
• Lead Sponsor: Fresenius Kabi Oncology Ltd

Brief Summary

A multicentre, randomized, open label, two-period, two-treatment, two-way crossover, single dose bioequivalence study comparing Temozolomide capsules 250 mg (Manufactured by: Fresenius Kabi Oncology Limited, India) to the reference listed drug Temodal® (Temozolomide) Capsules 250 mg (Manufactured by : SP Europe)  in Glioblastoma Multiforme or Anaplastic Astrocytoma patients under fasting condition.

**1.1** **Backgroundxml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /**

Temozolomide is an imidazotetrazine-alkylating agent with antitumor activity. It undergoes rapid chemical conversion in the systemic circulation at physiological pH to the active compound, monomethyl triazeno imidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.

 In the present study, the relative bioavailability of Temozolomide 250 mg from the test formulation in comparison to the reference formulation will be assessed after single oral dose administration to adult patients with Glioblastoma Multiforme or Anaplastic Astrocytoma, who in the opinion of their treating physicians are candidates for Temozolomide therapy.

 **1.2** **Study Design**

Open label, multicenter,  randomized, two-period, two-treatment, two-sequence, single dose, two-way crossover and comparative bioequivalence study in adult, male and/or female patients under fasting conditions.

**1.3** **Rationale For Study Design**

Temozolomide is a cytotoxic drug.  It would be unethical to do this study on healthy volunteers.  Therefore the bioequivalence study is proposed to be carried out on patients of malignant glioma such as glioblastoma multiforme or anaplastic astrocytoma, who in the opinion of their treating physicians are candidate for temozolomide therapy.

 The dosing and sampling regime is proposed to be built into the recommended treatment cycle of such patients.

 The recommended dosing regime is 5 consecutive days of therapy for 28-day treatment cycle for the initial chemotherapy cycle (150 mg /m2) and for subsequent chemotherapy cycles (200 mg/m2) for patients. (If the CTC non-haematological toxicity for Cycle 1 is Grade < 2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is > 1.5 x 109/l, and the thrombocyte count is > 100 x 109/l).

 In this study, single dose of 250 mg capsule each (Test and Reference) will be administered to patients at an interval of 24 hr.  As mean elimination half life (t1/2) of temozolomide is 1.8 hr., washout period of more than 18 hr is sufficient.  The remaining calculated dose will be given in divided doses over next 03 days as per the discretion of investigator.  Sampling for each period would go on till 12 hr to get adequate information on the required Pharmacokinetics profile of both the formulations.  Concomitant medications needed for patients would be allowed at the discretion of the treating investigator.

    **1.4** **Objective**

**Primary Objective:**

To characterize the pharmacokinetic profile of the sponsor’s test formulation (temozolomide 250 mg capsules) relative to that of reference formulation (TEMODAL 250 mg capsules) in adult, male and/or female patients under fasting conditions and to assess the bioequivalence.

 **Secondary Objective:**

To monitor the safety of the patients exposed to the Investigational Medicinal Product

**1.1** **Sampling Schedule**

A total of 17 blood samples each of 2.0 mL (4.0 mL in case of pre-dose sample) will be collected for each patient in each period.

 The venous blood samples will be withdrawn Pre-dose and 0.16 (10 min) 0.25 (15 min), 0.33 (20 min) 0.50 (30 min), 0.75 (45 min), 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00 and 12.00hours post-dose in each period administration.

 **1.2** **Total Blood Loss**

Not exceeding **108±10** mL for each patient for two periods as follows:

| | | | |

| --- | --- | --- | --- |

| PK assessment 32 post dose samples x 2.0 ml each

=

64 mL

|+

2 pre-dose samples x 4.0 ml each

=

08 mL

|+

32 x 0.5 mL discarded blood

=

16 mL

|+

For Screening

=

10 mL

|+

For ANC & Platelet count prior to dosing in period-I  & period II (2 ml for each period)

=

04 mL

|**+**

Safety assessment after period II and before check-out

**=**

06 mL

|**Total Blood Loss**

**=**

**108mL**

 **1.3** **Sample Collection**

Blood samples will be collected through an indwelling intravenous cannula (Venflon) placed in the forearm vein of the patients.  If required, it may also be collected through a fresh vein puncture.

 02 mL of blood per sample will be withdrawn using syringe / adaptor and transferred in to pre-labeled Vacutainers containing sodium heparin as anticoagulant. Vacutainers will be kept in wet ice bath during sample collection activity.

 Note: Predose blood sample will be collected within 60 minutes prior to dosing and post dose sample will be collected within ±2 min of the scheduled time.

**1.1** **Inclusion Criteria**

1)            Signed written informed consent for participation in the trial.

2)            Male or female patients within 18 to 65 years of age (both inclusive) requiring a dose of 225-275 mg of Temozolomide based on tumor type, BSA (body surface area), cycle number, and toxicity.

3)            Adult patients of newly diagnosed Glioblastoma Multiforme on/eligible for maintenance monotherapy phase with Temozolomide.

(or)

Malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, recurrent or progressive after standard therapy.

4)            Recovered from any toxic effects of previous chemotherapy as judged by the Investigator.

5)            There should a gap of 28 days (4 weeks) between the last day of radiotherapy and the day of randomization.

6)            Patients if already on steroids, then should be on a stable dose of steroids for at least 1 week prior to screening and should be stable throughout the study.

7)            Having a Body Mass Index (BMI) at least 17 calculated as weight in kg / height in m2

8)            Patients with a life expectancy of at least three months

9)            Able to comply with study requirement in opinion of Principal Investigator.

10)        Patient with adequate bone marrow, renal and hepatic function.

 

| | |

| --- | --- |

|**Body system**

**Parameters**

|Bone marrow function

ANC ³ 1.5 × 109/L,

Platelet count ³ 100 × 109/L

Haemoglobin  ≥ 9.0 g/dl

 11)        Able to intake food and medication

12)        ECOG Performance Status ≤ 2

13)        Male patients must agree to use an effective contraceptive method throughout the study and for 6 month after last dose of Temozolomide.

14)        In case of female patient of child bearing potentials the serum pregnancy test at screening visit and urine pregnancy test at day 0 must be negative.

15)        Sexually active women, unless surgically sterile (at least 6 months prior to Study drug administration) or postmenopausal for at least 12 consecutive months, must use an effective method of avoiding pregnancy for at least 4 weeks prior to study drug administration, during study and up to 30 days after the last dose of study drug.  Cessation of birth control after this point should be discussed with a responsible physician

**1.1** **Exclusion Criteria**

1)            Known hypersensitivity to temozolomide, Dacarbazine or any other ingredients of the formulation.

2)            Use of any chemotherapy drugs within 21 days prior to dosing

3)            History of drug/alcohol addiction

4)            History of smoking or tobacco chewing in last 3 months

5)            Known Galactose intolerant, Known  deficiency of the Lapp lactase or glucose-galactose malabsorption

6)            A positive hepatitis screen including hepatitis B surface antigen, HCV or HAV (IgM) antibodies.

7)            Patients with known HIV infection.

8)            The receipt of an investigational medicinal product within a period of 30 days prior to the first dose of investigational medicinal Product for the current study.

9)            Any other condition that, in the investigator’s judgment, might increase the risk to the patient or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study.

10)        Abnormal baseline findings considered by the investigator to indicate conditions that might affect study endpoints.

11)        Donation of blood (1 unit or 350 ml) within 90 days prior to receiving the first dose of investigational medicinal product for the current study.

Detailed Description

Not available

Study Timeline

• Study Start: 2012-05-07
• Last Update Posted: 2018-11-13

Recruitment & Eligibility

• Status: Completed
• Sex: All
• Target Recruitment: 40

Inclusion Criteria

• 1)Signed written informed consent for participation in the trial.
• 2)Male or female patients within 18 to 65 years of age (both inclusive) requiring a dose of 225-275 mg of Temozolomide based on tumor type, BSA (body surface area), cycle number, and toxicity.
• 3)Adult patients of newly diagnosed Glioblastoma Multiforme on/eligible for maintenance monotherapy phase with Temozolomide.
• (or) Malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, recurrent or progressive after standard therapy.
• 4)Recovered from any toxic effects of previous chemotherapy as judged by the Investigator.
• 5)There should a gap of 28 days (4 weeks) between the last day of radiotherapy and the day of randomization.
• 6)Patients if already on steroids, then should be on a stable dose of steroids for at least 1 week prior to screening and should be stable throughout the study.
• 7)Having a Body Mass Index (BMI) at least 17 calculated as weight in kg / height in m2 8)Patients with a life expectancy of at least three months 9)Able to comply with study requirement in opinion of Principal Investigator.

Exclusion Criteria

• 1)Known hypersensitivity to temozolomide, Dacarbazine or any other ingredients of the formulation.
• 2)Use of any chemotherapy drugs within 21 days prior to dosing 3)History of drug/alcohol addiction 4)History of smoking or tobacco chewing in last 3 months 5)Known Galactose intolerant, Known deficiency of the Lapp lactase or glucose-galactose malabsorption 6)A positive hepatitis screen including hepatitis B surface antigen, HCV or HAV (IgM) antibodies.
• 7)Patients with known HIV infection.
• 8)The receipt of an investigational medicinal product within a period of 30 days prior to the first dose of investigational medicinal Product for the current study.
• 9)Any other condition that, in the investigator’s judgment, might increase the risk to the patient or decrease the chance of obtaining satisfactory data needed to achieve the objectives of the study.

Study & Design

• Study Type: BA/BE
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
To characterize the pharmacokinetic profile of the sponsor’s test formulation (temozolomide 250 mg capsules) relative to that of reference formulation (TEMODAL 250 mg capsules) in adult, male and/or female patients under fasting conditions and to assess the bioequivalence	The venous blood samples will be withdrawn Pre-dose and 0.16 (10 min), 0.25 (15 min), 0.33 (20 min) 0.50 (30 min), 0.75 (45 min), 1.00, 1.25, 1.50, 2.00, 2.50, 3.00, 4.00, 6.00, 8.00, 10.00 and 12.00 hours post-dose in each period administration.

Secondary Outcome Measures

Name	Time	Method
To monitor the safety of the patients exposed to the Investigational Medicinal Product	NA

Trial Locations

Locations (11)

Belgaum Cancer Hospital; 🇮🇳 Belgaum, KARNATAKA, India

Bharat Cancer Hospital & Research Institute; 🇮🇳 Surat, GUJARAT, India

BIBI General Hospital & Cancer Centre; 🇮🇳 Hyderabad, ANDHRA PRADESH, India

Curie Manavata Cancer Centre; 🇮🇳 Nashik, MAHARASHTRA, India

Day care centre; 🇮🇳 Pune, MAHARASHTRA, India

Dr.Rai memorial medical centre; 🇮🇳 Chennai, TAMIL NADU, India

Govt. Medical College & Hospital, Panchakki Road, Aurangabad; 🇮🇳 Aurangabad, MAHARASHTRA, India

GreenCity Hopsital, Nagpur; 🇮🇳 Nagpur, MAHARASHTRA, India

Kailash cancer hospital and research Centre; 🇮🇳 Vadodara, GUJARAT, India

Lions Cancer Detection Centre; 🇮🇳 Surat, GUJARAT, India

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Belgaum Cancer Hospital

🇮🇳Belgaum, KARNATAKA, India

Dr Sandeep Madhwapathy

Principal investigator

09844033384

bch_belgaum@rediffmail.com