A Study to Evaluate the Safety of LAM561 Added to Standard of Care in Newly-diagnosed Glioblastoma Patients

NCT03867123 | Completed Phase 1

• 2 other identifiers: MIN-002-18012018-000317-21
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 3

Brief Summary

The purpose of this study is to determine the safety and tolerability of LAM561 added to first-line treatment for subjects with newly diagnosed glioblastoma (GBM), and to determine the highest safe dose of LAM561 administered orally when added to the concurrent phase of treatment with temozolomide (TMZ) and radiation therapy (RT) or when added to the maintenance phase of treatment with TMZ (once TMZ 200 g/m2/day is started).

Conditions

Glioblastoma (GBM)

Outcome Measures

Primary Outcomes (2)

• Safety and Tolerability of LAM561 in association with Standard of Care (Stupp Protocol)

  Incidence of Treatment-Emergent Adverse Events.

  10 to 12 weeks

• Maximum Tolerated dose (MTD)

  MTD of LAM561 administered with Standard of Care

  10 to 12 months

Secondary Outcomes (1)

• Plasma concentration of temozolomide (TMZ).

  First five days of cycle 2 of maintenance phase (each cycle is 4 weeks)

Study Arms (2)

Arm 1 (chemoradiation phase)

EXPERIMENTAL

Radiotherapy (RT) + temozolomide (TMZ) + LAM561 (during Concurrent phase - duration 6 weeks)\*: LAM561 will be initiated at the start of the concurrent phase and will be administered on a continuous daily basis together with TMZ and RT for 6 weeks at the selected dose, either 12 g/day (4 g tid), 8 g/day (4 g bid) or 4 g/day (4 g od). RT will be administered only during the concurrent phase, consisting of fractionated focal irradiation administered using 1.8- 2 Gy/fraction, daily for 5 days/week for 6 weeks, for a total dose of up to 60 Gy. TMZ will be administered during the concurrent phase at a starting dose of 75 mg/m2/day given daily for 6 weeks. \* One extra week may be allowed.

Drug: LAM561; Radiation: RT; Drug: TMZ

Arm 2 (maintenance phase)

EXPERIMENTAL

TMZ + LAM561 (during Maintenance phase with TMZ 200 mg/m2/day at Cycle 2 - duration 8 weeks): LAM561 will be initiated on day 2 of Cycle 2 of the maintenance phase, when TMZ 200 mg/m2/day is given and administered on a continuous basis for two 28-day cycles. LAM561 will be administered at the selected dose, either 12 g/day (4 g tid), 8 g/day (4 g bid) or 4 g/day (4 g od). TMZ will be administered at 200 mg/m2/day given daily the first 5 days for two 28-day cycles (if no toxicity is seen). In case of toxicity, TMZ dose may be reduced to 150 mg/m2/day at Cycle 3 to allow for recovery. Both arms will be followed by a 4-week safety follow-up

Drug: LAM561; Drug: TMZ

Interventions

LAM561 DRUG

Arm 1: Daily for 6 weeks. Arm 2: daily, two 28-day cycles

Arm 1 (chemoradiation phase); Arm 2 (maintenance phase)

RT RADIATION

In Arm 1: Fractionated focal irradiation of 1.8-2 Gy/fraction/day, 5 days/week, 6 weeks. Total dose up to 60 Gy

Also known as: radiotherapy

Arm 1 (chemoradiation phase)

TMZ DRUG

Arm 1: 75 mg/m2/day, daily, 6 weeks Arm 2: 200 mg/m2/day, daily the first 5 days of two 28-day cycles (in case of toxicity, TMZ dose may be reduced to 150 mg/m2/day at Cycle 3 to allow for recovery)

Also known as: temozolomide

Arm 1 (chemoradiation phase); Arm 2 (maintenance phase)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Glioblastoma (GBM) according to 2016 World Health Organization (WHO) Classification.
• Must have had a partial or complete surgical resection of the Grade 4 astrocytic tumor.
• Subjects in Arm 1 must have had no previous treatment except surgery (ie, no previous RT, local CT, or systemic therapy). Subjects must meet certain other eligibility requirements.
• Subjects in Arm 2 must have completed a standard first line regimen of concurrent TMZ and RT for newly diagnosed GBM patients, followed by a rest phase, and have not had any other previous CT except surgery (including any other regimens of RT and local or systemic CT). Progression and/or pseudoprogression should have been ruled out before starting Arm 2 as per usual clinical practice, with correct laboratory results (absolute neutrophile count ≥1.5 x 109/L, platelet count ≥ 100 x 109/L, non-haematological toxicity grade ≤ 2) at screening. Subjects must meet certain other eligibility requirements.
• Subjects must be able to undergo serial MRIs (computerized tomography may not be a substitute for magnetic resonance imaging \[MRI\]).
• Male or female ≥ 18 years old.
• Must have a Karnofsky performance status of ≥ 70% and the ability to swallow oral medication.
• Must have no other diagnosis of cancer malignancy (except surgically excised nonmelanoma skin cancer or carcinoma in situ of the cervix, or treated early stage prostate cancer, or a malignancy diagnosed ≥ 5 years previously with no current evidence of disease and no therapy within two years prior to enrolment on this study).
• Must be capable of understanding and complying with the protocol requirements.
• Contraception: All female patients will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age group and without other known or suspected cause), or have been sterilized surgically. Female patients of childbearing potential must agree to use two forms of highly effective contraception methods (a primary and a secondary method) during the study and for a period of 6 months following the last administration of the study drug. Male patients and their female partners, who are of childbearing potential and are not practicing total abstinence, must agree to use two forms of highly effective contraception methods (a primary and a secondary method) during the study and for a period of 6 months following the last administration of the study drug These contraception methods include oral, transdermal, systemic or implant contraception birth control, intra-uterine devices (IUD), abstinence and double barrier method such as diaphragm with spermicidal gel or other recommended double barrier methods screening.
• Written informed consent form signed before any study test or procedure.

You may not qualify if:

• Subject has received prior systemic CT or RT (Arm 1) or prior systemic CT other than TMZ (Arm 2), biologic agents, or any other type of investigational agent for the treatment of brain tumors.
• Subjects who have progressed on TMZ are not eligible (pseudoprogression ruled out as per usual clinical practice).
• Subject has evidence of acute intracranial or intratumoral hemorrhage \> Grade 1 by MRI. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin may enter the study.
• Subject has serious intercurrent illness such as: hypertension despite optimal treatment, or significant cardiac arrhythmias; or a recent history of serious disease such as symptomatic congestive heart failure, or abdominal fistula or gastrointestinal (GI) perforation within 6 months, prior to starting study treatment.
• Subject has had major surgery within 28 days prior to starting study treatment (except cancer resection surgery in arm 1), or had non water-tight dural closure during previous surgery, or has unhealed wounds from previous surgery.
• Subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
• Subject is pregnant or breastfeeding.
• Subject is known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at screening is not required).
• Subject has a previously-identified allergy or hypersensitivity to components of either the LAM561 or TMZ formulations.
• Subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

Sponsors & Collaborators

• Laminar Pharmaceuticals: lead

Study Sites (3)

Institut Catala d'Oncologia, Hospital Germans Trias I Pujol

Badalona, Catalonia, 08916, Spain

Location

Hospital Universitari de Girona Dr. Josep Trueta, Institut Català d'Oncologia

Girona, Catalonia, 17007, Spain

Location

Hospital Duran i Reynals, Institut Català d'Oncologia

L'Hospitalet de Llobregat, Catalonia, 08908, Spain

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

Radiotherapy; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Therapeutics; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Jordi Roma, MD

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  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2019
• First Posted: March 7, 2019
• Study Start: December 4, 2018
• Primary Completion: July 1, 2020
• Study Completion: July 1, 2020
• Last Updated: February 21, 2023

Record last verified: 2023-02

Locations

ES (3)