(Optimist): OPTmizing Advanced Stage HodgkIn LymphoMa patIentS Therapy

Sponsor

King Abdullah International Medical Research Center (Other)

Overall Status

Unknown status

CT.gov ID

NCT03527628

Collaborator

(none)

220

Enrollment

Location

Arms

48.5

Anticipated Duration (Months)

4.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a prospective, multi-center, open-label, phase II clinical trial, aims to assess the effectiveness of the combination ACVD (Adriamycin, Cyclophosphamide, Vinblastine and Dacarbazine) and BV (Brentuximab Vedotin) in PET-2 positive advanced-stage HL patients, in order to improve the overall long-term disease control in the entire cohort of advanced-stage HL.

Condition or Disease	Intervention/Treatment	Phase
Classical Hodgkin Lymphoma Hodgkin Lymphoma (Category) Hodgkin Disease Hodgkin Lymphoma	Drug: Adriamycin Drug: Cyclophosphamide Drug: Vinblastine Drug: Dacarbazine Drug: Brentuximab Vedotin Drug: ABVD	Phase 2

Detailed Description

With the aim of reducing Blemoycin pulmonary injury (BPI) , Bleomycin was withdrawn and substituted with Cyclophosphamide (ACVD cycle) in patients with a PET-2 negative. All advanced stage HL patients will receive 2 cycles of the standard treatment ABVD and assessed with PET-2 scan.

Knowing that Cyclophosphamide toxicities include cytopenias, amenorrhea and male infertility. These toxicities are mainly dependent on the total cumulative dose. Doses less than 4 g/m2 are not associated with sterility or major toxicity, doses higher than this can lead to azoospermia which was reversible in many cases therefore the cumulative dose will be used in this study is 3200 mg. Additionally, Brentuximab Vedotin has shown significant activity in relapsed refractory HL with minor toxicities.

PET scan after 2 cycles of ABVD has proven to be an excellent tool to identify patients that will have long term PFS of 95% when it is negative and only progression-free survival (PFS) of less than 15% when it is positive.

The primary endpoint of the study will be to assess the overall 3-Y PFS of the entire cohort of patients.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

220 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase II, Multicenter, Open Label Study of Treatment Intensification With ACVD and Brentuximab-Vedotin in Advanced-stage Hodgkin Lymphoma Patients With a Positive Interim PET Scan After 2 ABVD Cycles

Actual Study Start Date :

Jan 1, 2018

Anticipated Primary Completion Date :

Jan 15, 2021

Anticipated Study Completion Date :

Jan 15, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: Patients with PET-2 Negative Result After 2 ABVD cycles an interim PET-2 will be performed, and treatment will be adapted according to to PET results PET-2 negative patients will be treated with 4 cycles of ACVD (Adriamycin, Cyclophosphamide, Vinblastine And Dacarbazine)	Drug: Adriamycin 25mg/m2 Bolus injection via fast running drip of 0.9% NaCl in days 1 and 15 of each 28 day cycle. Other Names: Doxorubicin Drug: Cyclophosphamide 400mg/m2 Infusion in 500ml sodium chloride 0.9%over 30min. in days 1 and 15 of each 28 day cycle Other Names: Cytoxan® Neosar® Cycloblastin Revimmune Drug: Vinblastine 6mg/m2 Intravenous infusion in 50ml sodium chloride 0.9% over 10 minutes, in days 1 and 15 of each 28 day cycle Other Names: Velbe ® Drug: Dacarbazine 375mg/m2 Infusion in 500mls 0.9% NaCI over least 60mins. in days 1 and 15 of each 28 day cycle Other Names: DTIC Drug: ABVD All enrolled patients receive 2 cycles of ABVD (Adriamycin 25mg/m2, Bleomycin10,000units/m2, Vinblastine 6mg/m2 and Dacarbazine 375mg/m2) Other Names: (Adriamycin, Bleomycin, Vinblastine and Dacarbazine )
Other: Patients with PET-2 Positive Result After 2 ABVD cycles an interim PET-2 will be performed, and treatment will be adapted according to to PET results PET-2 positive patients will be treated with 4 cycles of ACVD with addition of Brentuximab Vedotin	Drug: Adriamycin 25mg/m2 Bolus injection via fast running drip of 0.9% NaCl in days 1 and 15 of each 28 day cycle. Other Names: Doxorubicin Drug: Cyclophosphamide 400mg/m2 Infusion in 500ml sodium chloride 0.9%over 30min. in days 1 and 15 of each 28 day cycle Other Names: Cytoxan® Neosar® Cycloblastin Revimmune Drug: Vinblastine 6mg/m2 Intravenous infusion in 50ml sodium chloride 0.9% over 10 minutes, in days 1 and 15 of each 28 day cycle Other Names: Velbe ® Drug: Dacarbazine 375mg/m2 Infusion in 500mls 0.9% NaCI over least 60mins. in days 1 and 15 of each 28 day cycle Other Names: DTIC Drug: Brentuximab Vedotin 1.2mg/kg Intravenous infusion, in days 1 and 15 of each 28 day cycle Other Names: ADCETRIS® SGN-35 Drug: ABVD All enrolled patients receive 2 cycles of ABVD (Adriamycin 25mg/m2, Bleomycin10,000units/m2, Vinblastine 6mg/m2 and Dacarbazine 375mg/m2) Other Names: (Adriamycin, Bleomycin, Vinblastine and Dacarbazine )

Arm

Intervention/Treatment

Other: Patients with PET-2 Negative Result

After 2 ABVD cycles an interim PET-2 will be performed, and treatment will be adapted according to to PET results PET-2 negative patients will be treated with 4 cycles of ACVD (Adriamycin, Cyclophosphamide, Vinblastine And Dacarbazine)

Drug: Adriamycin

25mg/m2 Bolus injection via fast running drip of 0.9% NaCl in days 1 and 15 of each 28 day cycle.

Other Names:

Doxorubicin

Drug: Cyclophosphamide

400mg/m2 Infusion in 500ml sodium chloride 0.9%over 30min. in days 1 and 15 of each 28 day cycle

Other Names:

Cytoxan®

Neosar®

Cycloblastin

Revimmune

Drug: Vinblastine

6mg/m2 Intravenous infusion in 50ml sodium chloride 0.9% over 10 minutes, in days 1 and 15 of each 28 day cycle

Other Names:

Velbe ®

Drug: Dacarbazine

375mg/m2 Infusion in 500mls 0.9% NaCI over least 60mins. in days 1 and 15 of each 28 day cycle

Other Names:

DTIC

Drug: ABVD

All enrolled patients receive 2 cycles of ABVD (Adriamycin 25mg/m2, Bleomycin10,000units/m2, Vinblastine 6mg/m2 and Dacarbazine 375mg/m2)

Other Names:

(Adriamycin, Bleomycin, Vinblastine and Dacarbazine )

Other: Patients with PET-2 Positive Result

After 2 ABVD cycles an interim PET-2 will be performed, and treatment will be adapted according to to PET results PET-2 positive patients will be treated with 4 cycles of ACVD with addition of Brentuximab Vedotin

Drug: Adriamycin

25mg/m2 Bolus injection via fast running drip of 0.9% NaCl in days 1 and 15 of each 28 day cycle.

Other Names:

Doxorubicin

Drug: Cyclophosphamide

400mg/m2 Infusion in 500ml sodium chloride 0.9%over 30min. in days 1 and 15 of each 28 day cycle

Other Names:

Cytoxan®

Neosar®

Cycloblastin

Revimmune

Drug: Vinblastine

6mg/m2 Intravenous infusion in 50ml sodium chloride 0.9% over 10 minutes, in days 1 and 15 of each 28 day cycle

Other Names:

Velbe ®

Drug: Dacarbazine

375mg/m2 Infusion in 500mls 0.9% NaCI over least 60mins. in days 1 and 15 of each 28 day cycle

Other Names:

DTIC

Drug: Brentuximab Vedotin

1.2mg/kg Intravenous infusion, in days 1 and 15 of each 28 day cycle

Other Names:

ADCETRIS®

SGN-35

Drug: ABVD

All enrolled patients receive 2 cycles of ABVD (Adriamycin 25mg/m2, Bleomycin10,000units/m2, Vinblastine 6mg/m2 and Dacarbazine 375mg/m2)

Other Names:

(Adriamycin, Bleomycin, Vinblastine and Dacarbazine )

Outcome Measures

Primary Outcome Measures

]Progression Free Survival (PFS) [3 years]
PFS is estimated from the date of diagnosis until the date of first disease progression or relapse, death for any cause. Superior overall 3 year progression-free survival of patients with PET 2 positive after 2 cycles of ABVD with ACVD and BV compared to historical control of ABVD treated patients and PET 2 negative patients with ACVD only after 2 cycles of ABVD.

Secondary Outcome Measures

Overall Survival (OS) [5 years]
Superior overall survival of PET 2 positive patients treated with ACVD + BV after 2 cycles of ABVD and PET 2 negative treated with ACVD after 2 cycles of ABVD. It is estimated from the date of diagnosis up to study completion or death, whichever came first, assessed up to 5 years.

Other Outcome Measures

Reduction of lung toxicity [6 months]
The ability of ACVD to reduce lung toxicity as compared to ABVD by performing a pulmonary function test (PFT) at baseline and end of treatment
Overall toxicity [6 months]
The feasibility of the entire program in terms of grade 3 or 4 NCICTCAE or WHO toxicity

Eligibility Criteria

Criteria

Ages Eligible for Study:

14 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

All the following parameters should be met
Newly diagnosed untreated ,histologically proven CD30 positive classical Hodgkin Lymphoma (cHL)
Advanced stage (Stage IIB to IVB) as defined by Ann Arbor Staging System (Appendix 1)
Age ≥ 14, < 60 years
ECOG performance status 0-2
Written informed consent for the trial
Adequate contraceptive precautions for all patients of childbearing potential
All prognostic group

Exclusion Criteria:

Any of the following:
Pregnant or lactating women.
Presence of the following:

Heart failure with LVEF <50%
Liver enzymes, >2 ULN not attributed to Hodgkin Lymphoma.
Another malignancy that is currently clinically significant or requires active intervention

Early-stage disease (Stage I- IIA).
Patients who are already participating to another clinical trial.
Known history of HIV seropositive status
ECOG performance status 3-4
Creatinin clearance <50 ml/min
Prior treatment for Hodgkin Lymphoma excluding steroids
Medical or psychiatric conditions compromising the patient's ability to give informed consent
Patients with serious active infection
Pre-existing peripheral neuropathy (grade 2 or more).