UNITE Study: Understanding New Interventions With GBM ThErapy

Study Overview
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Brief Summary
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The objective of this study was to evaluate the effect of several ophthalmologic prophylactic treatment strategies for the management of ocular side effects (OSEs) in participants with epidermal growth factor receptor (EGFR)-amplified glioblastoma (GBM) who were being treated with depatuxizumab mafodotin (ABT-414).

Detailed Description
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This Phase 3b open-label, randomized, exploratory study included 2 phases during the treatment period: chemoradiation therapy (radiation plus temozolomide [RT/TMZ]) and adjuvant therapy (TMZ). All participants received depatuxizumab mafodotin during both phases of the treatment period plus 1 of 3 prophylactic ophthalmologic treatments (standard steroids; standard steroids with vasoconstrictors and cold compress; and enhanced steroids with vasoconstrictors and cold compress. The study comprised a screening period of up to 7 weeks after surgery, a 6-week concomitant Chemoradiation Phase, an Adjuvant Phase beginning approximately 4 weeks after completion of chemoradiation, and a Follow-Up Phase.

Official Title
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Phase 3b Study for Management of Ocular Side Effects in Subjects With EGFR-amplified Glioblastoma Receiving Depatuxizumab Mafodotin (ABT-414)

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Steroid eye drops
* Drug: Vasoconstrictor eye drops
* Other: Cold compress
* Drug: Ophthalmic steroid ointment
* Drug: Depatuxizumab mafodotin
* Drug: Temozolomide
* Radiation: Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed glioblastoma (GBM) histologically proven, World Health Organization (WHO) grade IV GBM or WHO grade IV gliosarcoma Tumors must demonstrate epidermal growth factor receptor (EGFR) amplification Tumors must be supratentorial in location Participant must have recovered from the effects of surgery, postoperative infection, and other complications; has no significant post-operative hemorrhage Participant has a Karnofsky performance status (KPS) of 70 or higher Participant has adequate bone marrow, renal, and hepatic function Electrocardiogram without evidence of acute cardiac ischemia ≤ 21 days prior to randomization Participant has a life expectancy of ≥ 3 months Exclusion Criteria: Participant has received prior chemotherapy or radiotherapy for cancer of the head and neck region Participant has received prior treatment with Gliadel wafers or any other intratumoral or intracavitary treatment Participant has hypersensitivity to any component of temozolomide or dacarbazine Participant has received anti-cancer therapy (including chemotherapy, immunotherapy, radiotherapy, hormonal, biologic, or any investigational therapy) within 5 years of Study Day 1 Participant has clinically significant uncontrolled condition(s) as described in the protocol Participant has any medical condition which in the opinion of the investigator places the participant at an unacceptably high risk for toxicities Participant has had another active malignancy within the past 3 years except for any cancer considered cured or non-melanoma carcinoma of the skin Participant has a history of herpetic keratitis Participant is not suitable for receiving ocular steroids with conditions as described in the protocol Participant has had laser-assisted in situ keratomileusis (LASIK) procedure within the last 1 year or cataract surgery within the last 3 months Participant has a visual condition that compromises the ability to accurately measure visual acuity or assess visual activities of daily living (vADLs) Participant has hepatitis B virus or hepatitis C virus infection Participant not receiving treatment with highly active antiretroviral therapy (HAART) when positive for human immunodeficiency virus (HIV)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Standard Steroids<br>Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days | Drug: Steroid eye drops<br>* Solution, eye drop<br>Drug: Depatuxizumab mafodotin<br>* During the Chemoradiation Phase, participants were to receive depatuxizumab mafodotin at 2.0 mg/kg IV infusion over 30 - 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen). During the Adjuvant Therapy Phase, participants were to receive depatuxizumab mafodotin at 1.25 mg/kg on Day 1 (± 2 days) and Day 15 (± 2 days) of each 28-day cycle as a 30 - 40 minute infusion for 12 cycles.<br>* Other names: ABT-414;Drug: Temozolomide<br>* Temozolomide was to be administered according to the local standard of care. Duration of treatment was to be 6 - 12 cycles in the adjuvant phase and at the discretion of the investigator as supported by local standard of care.<br>Radiation: Radiation<br>* Radiation therapy treatment planning and administration was to be performed as per local institutional guidelines.<br>|
| Experimental: Standard Steroids + Vasoconstrictor + Cold Compress<br>Steroid eye drops: 1 drop each eye, 3 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 - 6 times on day of infusion in total (5 - 10 minutes before infusion; at end of infusion; and 2 - 4 times during the remainder of the infusion day). Continuing 4 - 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 - 3 with each depatuxizumab mafodotin infusion. The cold compress was to be applied in increments no longer than 30 min (could be shorter if the participant was uncomfortable). | Drug: Steroid eye drops<br>* Solution, eye drop<br>Drug: Vasoconstrictor eye drops<br>* Solution, eye drop<br>Other: Cold compress<br>* Cold compress<br>Drug: Depatuxizumab mafodotin<br>* During the Chemoradiation Phase, participants were to receive depatuxizumab mafodotin at 2.0 mg/kg IV infusion over 30 - 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen). During the Adjuvant Therapy Phase, participants were to receive depatuxizumab mafodotin at 1.25 mg/kg on Day 1 (± 2 days) and Day 15 (± 2 days) of each 28-day cycle as a 30 - 40 minute infusion for 12 cycles.<br>* Other names: ABT-414;Drug: Temozolomide<br>* Temozolomide was to be administered according to the local standard of care. Duration of treatment was to be 6 - 12 cycles in the adjuvant phase and at the discretion of the investigator as supported by local standard of care.<br>Radiation: Radiation<br>* Radiation therapy treatment planning and administration was to be performed as per local institutional guidelines.<br>|
| Experimental: Enhanced Steroids + Vasoconstrictor + Cold Compress<br>Enhanced steroid eye drops: 1 drop each eye, 6 times/day, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Ophthalmic Steroid Ointment; applied to each eye once daily before sleep, starting 2 days prior to depatuxizumab mafodotin infusion and continuing until 4 days after infusion, for a total of 7 days; Vasoconstrictor Eye Drops: 1 drop each eye 4 - 6 times on day of infusion in total (5 - 10 minutes before infusion; at end of infusion; and 2 - 4 times during the remainder of the infusion day). Continuing 4 - 6 times/day on Day 1 and Day 2 after each depatuxizumab mafodotin infusion; Cold Compress: Starting 5 minutes prior to start of infusion and continuing for 30 minutes past end of infusion, and then use at least 2 hours total/day on Days 1 - 3 with each depatuxizumab mafodotin infusion. Cold compress was to be applied in increments no longer than 30 min (could be shorter if the patient is uncomfortable). | Drug: Steroid eye drops<br>* Solution, eye drop<br>Drug: Vasoconstrictor eye drops<br>* Solution, eye drop<br>Other: Cold compress<br>* Cold compress<br>Drug: Ophthalmic steroid ointment<br>* Ointment<br>Drug: Depatuxizumab mafodotin<br>* During the Chemoradiation Phase, participants were to receive depatuxizumab mafodotin at 2.0 mg/kg IV infusion over 30 - 40 minutes once every 2 weeks (Day 1 of Weeks 1, 3, and 5 of the 6-week regimen). During the Adjuvant Therapy Phase, participants were to receive depatuxizumab mafodotin at 1.25 mg/kg on Day 1 (± 2 days) and Day 15 (± 2 days) of each 28-day cycle as a 30 - 40 minute infusion for 12 cycles.<br>* Other names: ABT-414;Drug: Temozolomide<br>* Temozolomide was to be administered according to the local standard of care. Duration of treatment was to be 6 - 12 cycles in the adjuvant phase and at the discretion of the investigator as supported by local standard of care.<br>Radiation: Radiation<br>* Radiation therapy treatment planning and administration was to be performed as per local institutional guidelines.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Required a Change in Ocular Side Effect (OSE) Management | Inadequate control of ocular side effects (OSE) was defined as either a ≥ 3-line decline from baseline (≥ +0.3 on LogMAR scale) in visual acuity (with baseline correction determined at the screening ophthalmology visit)) or ≥ Grade 3 OSE severity on the Corneal Epithelial Adverse Event (CEAE) scale. | Within 8 weeks after the initial dose of depatuxizumab mafodotin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Change From Baseline on the Logarithm of the Minimum Angle of Resolution (LogMAR) Scale | The LogMAR scale measures visual acuity on a continuous scale, with a LogMAR value of 0 equivalent to 20/20 visual acuity. Normal vision is considered to be from -0.2 - 0.1; higher values indicate visual impairment. The baseline observation is defined as the last non-missing measurement collected prior to the first dose of depatuxizumab mafodotin. | Within 8 weeks after the initial dose of depatuxizumab mafodotin | 
| Time to Bandage Contact Lens (BCL) Intervention | The time to initiation of bandage contact lenses for those participants who required intervention due to inadequate control of ocular side effects (OSE) was calculated. | Up to 9 months after the first dose of depatuxizumab mafodotin | 
| Number of Participants With Depatuxizumab Mafodotin Dose Modifications Due to Ocular Side Effects (OSE) | Dose modifications included depatuxizumab mafodotin withdrawal, interruption, and reductions in dose initiated due to OSEs. | From the first dose of study drug until 49 days after last depatuxizumab mafodotin administration, up to 47 weeks | 
| Cumulative Dose of Depatuxizumab Mafodotin Received During Chemoradiation and During Adjuvant Treatment | The cumulative dose of depatuxizumab mafodotin administered was tabulated. | Up to 9 months | 
| Treatment-Emergent Corneal Epithelial Adverse Event (CEAE) Grade at Each Visit | The corneal epithelial adverse event (CEAE) rating scale is designed to record symptoms associated with corneal epitheliopathy caused by antibody-drug conjugates and to grade the severity of findings. The overall CEAE grade is measured on a scale of 0 to 5, with higher values being more severe, reflecting the impact of corneal abnormalities on visual activities of daily living (ADLs). Additional detailed information is collected for specific domains that are commonly affected, with the following ranges (each in order of increasing severity): ocular discomfort (0 - 4), photophobia (0 - 3), and reading (1 - 3). | Up to 47 weeks | 
| Change From Baseline In Logarithm of the Minimum Angle of Resolution (LogMAR) Scale After Bandage Contact Lens (BCL) Intervention | The change on the LogMAR Scale from last assessment prior to BCL intervention to 2 weeks after BCL intervention was calculated. The LogMAR scale measures visual acuity on a continuous scale, with a LogMAR value of 0 equivalent to 20/20 visual acuity. Normal vision is considered to be from -0.2 - 0.1; higher values indicate visual impairment. | From the last assessment prior to BCL intervention to 2 weeks after BCL intervention | 
| Percentage of Participants That Recovered to <3-line Decline From Baseline (≤ +0.3 LogMAR) in Visual Acuity After Bandage Contact Lens (BCL) Intervention | Recovery was defined as return to <3-line decline from baseline (≤ +0.3 LogMAR) in visual acuity after BCL intervention. | From the last assessment prior to BCL intervention to the end of BCL intervention | 
| Number of Participants With Depatuxizumab Mafodotin Dose Modifications to Ocular Side Effects After Bandage Contact Lens (BCL) Intervention | Dose modifications included depatuxizumab mafodotin withdrawal, interruption, and reductions in dose initiated due to OSEs after BCL intervention. | From the last assessment prior to BCL intervention to the end of BCL intervention, up to 38 weeks | 
| Time to Restart Depatuxizumab Mafodotin if Interrupted Due to Ocular Side Effects After Bandage Contact Lens (BCL) Intervention | The time to restart depatuxizumab mafodotin treatment if it was interrupted due to ocular side effects after BCL Intervention was tabulated. | From the last assessment prior to BCL intervention to the end of BCL intervention | 
| Treatment Emergent Corneal Epithelial Adverse Event (CEAE) Grade at Each Visit After Bandage Contact Lens (BCL) Intervention | The corneal epithelial adverse event (CEAE) rating scale is designed to record symptoms associated with corneal epitheliopathy caused by antibody-drug conjugates and to grade the severity of findings. The overall CEAE grade is measured on a scale of 0 to 5, with higher values being more severe, reflecting the impact of corneal abnormalities on visual activities of daily living (ADLs). Additional detailed information is collected for specific domains that are commonly affected, with the following ranges (each in order of increasing severity): ocular discomfort (0 - 4), photophobia (0 - 3), and reading (1 - 3). | From the last assessment prior to BCL intervention to the end of BCL intervention, up to 38 weeks | 
| Time to Ocular Side Effect (OSE) Symptom Resolution After Drug Discontinuation (Reversibility) | The time from discontinuation of depatuxizumab mafodotin to OSE symptom resolution (reversibility) was to be recorded. | From the first dose of study drug until 49 days after last depatuxizumab mafodotin administration, up to 47 weeks | 
| Time to Re-initiation of Depatuxizumab Mafodotin After Dose Interruption | The time from dose interruption until re-initiation or permanent discontinuation of depatuxizumab mafodotin was to be recorded. | Up to 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glioblastoma Multiforme (GBM), Cancer, Chemoradiation therapy, Epidermal growth factor receptor-amplified glioblastoma, Radiation, Temozolomide