Clinical trial NCT03423628: A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer
Official title: A Phase I, Multicentre Study to Assess the Safety, Tolerability, and Pharmacokinetics of Ascending Doses of AZD1390 in Combination With Radiation Therapy in Patients With Glioblastoma Multiforme and Brain Metastases From Solid Tumors.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Recurrent Glioblastoma Multiforme
Primary Glioblastoma Multiforme
Brain Neoplasms, Malignant
Leptomeningeal Disease (LMD)
Keywords: glioblastoma
Ataxia-telangiectasia mutated kinase (ATM) inhibition
radiation therapy
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2018-02-06
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: AZD1390 will be administered to patients in three different Arms (A, B and C), with each arm receiving standard of care radiation therapy (RT) for their disease setting.

In arms A and C, AZD1390 will be administered in three cycles: Cycle 0 (before RT), Cycle 1 (during RT) and Cycle 2 (after RT).

In arm B, AZD1390 will be administered in cycle 1 only (during RT). Within each arm, AZD1390 will be administered in dose escalating cohorts, first in an intermittent and then in a consecutive fashion, to achieve daily administration prior to RT.

\*\*Arm B has now closed to recruitment\*\*

For Arm A, there is an optional food effect assessment during cycle 0. \*Note: the optional food effect assessment is currently not open to recruitment\*
Primary purpose: TREATMENT

Brief summary: This study will test an investigational drug called AZD1390 in combination with radiation therapy for the treatment of brain tumors. This is the first time AZD1390 is being given to patients. This study will test safety, tolerability and PK (how the drug is absorbed, distributed and eliminated) of ascending doses of AZD1390 in combination with distinct regimens of radiation therapy

Detailed description: This first time-in patients (FTIP), open-label, multicentre study of AZD1390 will be conducted in the United States, the United Kingdom and Japan. It consists of three treatment arms: Arm A, B, C. The Japan dose confirmation part (Japan part) is a sub-study of Arm A. Sites from Japan will only participate in the Japan part. This Phase 1 study will assess safety and tolerability of AZD1390 in combination with radiation therapy (RT) in brain malignancies. The combination cohorts have been designed to assess escalating cumulative doses of AZD1390 in settings with 3 different radiation treatment regimens:

* Arm A and Japan Part: 35 Gy over 2 weeks with intensity-modulated radiation therapy (IMRT) in patients with recurrent Glioblastoma Multiforme (GBM)
* Arms B: 30 Gy over two weeks with whole brain radiation therapy (WBRT)/ partial brain radiation therapy (PBRT) in patients with brain metastases. \*\*Arm B has now closed to recruitment\*\*
* Arm C: 60 Gy over 6 weeks (IMRT) in patients with primary GBM Each arm provides standard of care RT for the disease setting indicated with the experimental agent being administered in dose escalating cohorts.

Eligibility criteria: Inclusion Criteria:

* Provision of formalin-fixed paraffin embedded tissue sample from primary or metastatic disease
* Karnofsky Performance Score of ≥60.
* Additional Inclusion Criteria Specific for Arm A and Japan:

  * Histologically proven diagnosis of GBM. Patients who have had RT for low-grade glioma (LGG) or grade 3 glioma and have subsequently relapsed to histologically confirmed GBM can be considered
  * A radiological diagnosis of recurrent/relapsed or progressive disease according to RANO criteria.
  * Completion of first-line radiation at least 6 months prior to Cycle 1 Day 1.
  * Patients with tumor-induced seizures must be well controlled on a stable anti-epileptic treatment
  * Willing to receive anti-epileptic prophylaxis for the duration of study drug administration.
* Additional Inclusion Criteria Specific for Arm B:

\*\*Arm B has now closed to recruitment\*\*

* Histologically proven diagnosis of solid tumor malignancy and Magnetic Resonance (MR) imaging documenting brain lesions.
* Not eligible for Stereotactic Radiosurgery (SRS) treatment of brain tumor.
* Patient has not received any previous brain RT to the area that is to be irradiated. Prior PBRT may be allowed if there is not significant overlap between the prior and new radiation fields.
* Non-CNS malignant disease must be sufficiently controlled so that patients can be without additional systemic therapy for the required washout period before starting therapy until 5 days after the end of RT. Required washout period before starting the first dose of AZD1390 (Cycle 1) is 28 days for immune checkpoint inhibitors and 7 days for all other agents
* Not received radiation to the lung fields within the past 8 weeks.
* No history of seizures related to the brain metastases or LMD.
* Receiving PBRT (rather than WBRT) during Cycle 1 as standard of care for brain metastases

  • Additional Inclusion Criteria Specific for Arm C:
* Histologically proven primary diagnosis of GBM with unmethylated O6-methylguanine-DNA methyltransferase (MGMT). Grade 4 astrocytoma or histology with molecular features of GBM can be considered.
* Determination of MGMT promoter status by methylation-specific polymerase chain reaction (PCR) or pyrosequencing per local institutional guidelines is required to assess eligibility for this Arm.
* Patients will have to undergo mutational testing for Isocitrate dehydrogenase 1 (IDH1) on a tumor specimen before entering study. Patients are eligible for Arm C regardless of their IDH1 mutational status.
* No history of uncontrolled seizures after surgery for primary GBM (despite adequate antiepileptic therapy) or with need for concurrent administration of more than 2 antiepileptic drugs.
* Willing to receive anti-epileptic prophylaxis for the duration of study drug administration

Additional Inclusion criteria for Food Effect Assessment (Arm A) (Not applicable for Japan part):

* For the fed assessment portion: fast overnight (for at least 10 hours) prior to consuming a high-fat meal consisting of approximately 800 to 1000 calories, with around 54% of the calories coming from fat.
* For the fasted assessment portion: fast overnight (for at least 10 hours prior to dosing) and until 4 hours after dosing.

\*Note: the optional food effect assessment is currently not open to enrolment\*

Exclusion Criteria:

* Administration of chemotherapy or any investigational drug in the 28 days or carmustine (CCNU) or lomustine (BCNU) in the 6 weeks prior to receiving the first dose of treatment in Arms A and C. Administration of checkpoint inhibitors within 28 days prior to first dose of treatment and any other agent within 7 days of beginning study treatment in Arm B. Hormonal therapies are allowed during study treatment for patients in Arm B.
* History of severe brain-injury or stroke.
* Patient not eligible for sequential MRI evaluations are not eligible for this study.
* History of epileptic disorder or any seizure history unrelated to tumor
* Treatment with Strong inhibitors or inducers of CYP3A4 within 2 weeks prior to receiving study drug
* Concurrent therapy with other seizurogenic medications.
* Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
* Concurrent severe and/or uncontrolled medical condition (e.g., severe COPD).
* Prior treatment with pneumotoxic drugs, e.g. busulfan, bleomycin, within the past year. If prior therapy in lifetime, then excluded if history of pulmonary toxicities from administration. Patients who have received treatment with nitrosoureas (e.g., carmustine, lomustine) in the year before study entry without experiencing lung toxicity are allowed on study.
* History or presence of myopathy or raised creatine kinase (CK) \>5 x upper limit of normal (ULN) on 2 occasions at screening.
* Cardiac dysfunction defined as: Myocardial infarction within six months of study entry, NYHA (New York Heart Association) Class II/III/IV heart failure, unstable angina, unstable cardiac arrhythmias
* Evidence of severe pulmonary infections, as judged by the investigator (For Japan part only this includes active infection including tuberculosis, chronic active or uncontrolled Hep B or Hep C)
* With the exception of alopecia, any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 4.03) Grade 1 at the time of starting study treatment and patients with chronic Grade 2 unresolved toxicities may be eligible Additional exclusion criteria for Arm A and Japan Part
* Has previously received ATM inhibitor with concurrent RT

Additional Exclusion criteria for Food Effect Assessment (Arm A) (Not applicable for the Japan Part):

* Diabetes Type I, Type II, or steroid-induced diabetes.
* Undergoing systemic steroid treatment \*Note: the optional food effect assessment is currently not open to enrolment\*

Primary outcomes:
measure: Incidence of dose-limiting toxicities (DLTs)
timeFrame: From the start of treatment until the end of the DLT period (approximately 6 weeks for Arm A, 3 weeks for Arm B and 10 weeks for Arm C)
measure: Incidence of adverse events (AEs) and serious adverse events (SAEs)
timeFrame: From the start of treatment until the patient is off study (approximately 1 year for all Arms)
Secondary outcomes:
measure: Event free survival (EFS) for Arms A and C only
timeFrame: From the start of treatment until the patient is off study (approximately 1 year)
measure: Objective response rate defined by RANO criteria for Arms A and C only
timeFrame: Every 8 weeks starting from 4 weeks after RT until the end of the study (approximately 1 year)
measure: Objective response rate defined by RANO-BM criteria for Arm B only. **Arm B has now closed to recruitment**
timeFrame: From screening until the patient is off study, approximately 8 weeks
measure: Objective response rate defined by RECIST 1.1 criteria for Arm B only. **Arm B has now closed to recruitment**
timeFrame: From screening until the patient is off study, approximately 8 weeks
measure: Maximum Observed Plasma Concentration (Cmax) of AZD1390
timeFrame: At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arm A, 2 weeks for Arm B and 9 weeks for Arm C)
measure: Time to observed Cmax (Tmax) for AZD1390
timeFrame: At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arm A, 2 weeks for Arm B and 9 weeks for Arm C)
measure: Area under the plasma concentration-time curve (AUC) for AZD1390
timeFrame: At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arm A, 2 weeks for Arm B and 9 weeks for Arm C)
measure: Renal clearance (CLR) for AZD1390
timeFrame: At predefined intervals throughout the AZD1390 treatment period (approximately 5 weeks for Arm A and 9 weeks for Arm C)
measure: Overall survival for Arms A and C only
timeFrame: From start of treatment until the patient dies, withdraws or the end of study is reached (approximately 15 months after last patient has started treatment)
measure: Assessment of the food effect of AZD1390 at the MTD for Arm A (if conducted)
timeFrame: At two predefined intervals throughout cycle 0 (approximately 7 to 9 days)
Other outcomes:
Locations:
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: New York
country: United States
facility: Research Site
state: New York
city: Pittsburgh
country: United States
facility: Research Site
state: Pennsylvania
city: Richmond
country: United States
facility: Research Site
state: Virginia
city: Chuo-ku
country: Japan
facility: Research Site
city: Hidaka-shi
country: Japan
facility: Research Site
city: Kyoto-shi
country: Japan
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Leeds
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Patrick Wen
role: PRINCIPAL_INVESTIGATOR
affiliation: Memorial Sloan Kettering Cancer Center
name: Brandon Imber
role: PRINCIPAL_INVESTIGATOR
affiliation: VCU Massey Cancer Center
name: Mariza Daras
role: PRINCIPAL_INVESTIGATOR
affiliation: UPMC Hospital Radiation Oncology
name: Jan Drappatz
role: PRINCIPAL_INVESTIGATOR
affiliation: Massachusetts General Hospital
name: Deborah Forst
role: PRINCIPAL_INVESTIGATOR
affiliation: Beatson West of Scotland Cancer Centre
name: Anthony Chalmers
role: PRINCIPAL_INVESTIGATOR
affiliation: Cambridge University Hospitals NHS Foundation Trust
name: Rajesh Jena
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Leeds
name: Susan Short
role: PRINCIPAL_INVESTIGATOR
References: