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A Study to Assess the Safety and Tolerability of AZD1390 Given With Radiation Therapy in Patients With Brain Cancer

Study Purpose

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

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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: - 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 study entry.
  • - 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.

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.
- 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

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT03423628
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

AstraZeneca
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Patrick WenJonathon YangAlicia ZukasDavid Anthony ClumpDeborah ForstAnthony ChalmersGary DohertySusan Short
Principal Investigator Affiliation Dana-Farber Cancer InstituteMemorial Sloan Kettering Cancer CenterVCU Massey Cancer CenterUPMC Hospital Radiation OncologyMassachusetts General HospitalBeatson West of Scotland Cancer CentreCambridge University Hospitals NHS Foundation TrustUniversity of Leeds
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Industry
Overall Status Recruiting
Countries United Kingdom, United States
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Recurrent Glioblastoma Multiforme, Primary Glioblastoma Multiforme, Brain Neoplasms, Malignant, Leptomeningeal Disease (LMD)
Additional Details

This first time-in patients (FTIP), open-label, multicentre study of AZD1390 will be conducted in the United States and in the United Kingdom, and it consists of three treatment arms: Arm A, B, C. 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: 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.

Arms & Interventions

Arms

Experimental: AZD1390 + Radiation Therapy

AZD1390 + Radiation Therapy

Interventions

Radiation: - Radiation Therapy

Arm A: 35 Gy of Intensity-modulated radiation therapy (IMRT) administered at daily fractions of 3.5 Gy over 10 fractions (2 weeks) Arm B: 30 Gy of whole brain radiation therapy (WBRT) or partial brain radiation therapy (PBRT) administered at daily fractions of 3 Gy over 10 fractions (2 weeks). **Arm B has now closed to recruitment** Arm C: 60 Gy of intensity-modulated radiation therapy (IMRT) administered at daily fractions of 2 Gy over 30 fractions (6 weeks)

Drug: - AZD1390

AZD1390 Administered in 3 Cycles depending on arm: Cycle 0 (arms A and C): 1 dose prior to Radiation Therapy. Cycle 1 (all arms): Intermittent or continuous dosing during Radiation Therapy (except for first 2 cohorts of Arm A). Cycle 2 (arms A and C): 2 weeks adjuvant treatment after Radiation Therapy.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Research Site, Boston, Massachusetts

Status

Recruiting

Address

Research Site

Boston, Massachusetts, 02114

Research Site, Boston, Massachusetts

Status

Recruiting

Address

Research Site

Boston, Massachusetts, 02215

Research Site, New York, New York

Status

Recruiting

Address

Research Site

New York, New York, 10065

Research Site, Pittsburgh, Pennsylvania

Status

Recruiting

Address

Research Site

Pittsburgh, Pennsylvania, 15232

Research Site, Richmond, Virginia

Status

Recruiting

Address

Research Site

Richmond, Virginia, 23294

International Sites

Research Site, Cambridge, United Kingdom

Status

Recruiting

Address

Research Site

Cambridge, , CB2 0QQ

Research Site, Glasgow, United Kingdom

Status

Recruiting

Address

Research Site

Glasgow, , G12 0YN

Research Site, Leeds, United Kingdom

Status

Recruiting

Address

Research Site

Leeds, , LS9 7TF