Human stem cell derived neuron
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A Study of AZD9574 as Monotherapy and in Combination with Anti-Cancer Agents in Participants with Advanced Solid Malignancies (CERTIS1)

Summary

This phase I/IIa study in patients with recurrent IDH-mutant glioma will investigate the safety and preliminary efficacy of AZD9574 in combination with temozolomide (TMZ).

IDH-mutant gliomas seem to be more sensitive to first-line standard of care treatments like TMZ, a type of chemotherapy that kills cells by modifying the structure of their DNA through the addition of alkyl groups. AZD9574 is a novel brain penetrant drug that potently and selectively inhibits and traps PARP1, an enzyme involved in a cell's DNA repair processes. Combining TMZ with this PARP inhibitor may be a more effective treatment option for patients with IDH-mutant glioma.

Inclusion Criteria
  1. Participants must be suitable for treatment with TMZ.
  2. Participants must have IDH1/2-mutant glioma.
  3. Participants should have progressive disease after prior radiation therapy and one prior line of alkylating chemotherapy (eg, PCV or TMZ) for their disease. Disease progression or recurrence should have occurred more than 6 months post radiation therapy or 6 months after the end of chemotherapy.
  4. Recurrent disease must be evaluable by MRI (either measurable or non-measurable by RANO-HGG or RANO-LGG). Participants who have undergone surgical resection for recurrence are eligible as long as they have residual disease that is evaluable.
  5. Formalin-fixed, paraffin-embedded tumor sample from the primary cancer must be available for central testing of IDH1/2 and nuclear ATRX loss of function mutation status, 1p/19q co-deletion assessment and MGMT promoter methylation assessment. If there is no written confirmation of the availability of an archived tumor sample prior to enrollment, the participants are not eligible for the study.
  6. Female participants of childbearing potential must have a negative pregnancy test result at screening and prior to each cycle administration of AZD9574 and TMZ. If sexually active with a non-sterilized male partner, must use at least one highly effective method of birth control from screening to approximately 6 months after the last dose of study intervention. Female participants must not breastfeed and must not donate or retrieve ova for their own use from screening to approximately 6 months after the last dose of study intervention.
  7. Adequate organ and marrow function:
    1. Hematological
      1. Hemoglobin: ≥ 9.0 g/dL (5.59 mmol/L)
      2. Absolute neutrophil count: ≥ 1.7 × 109/L (1,500 per mm3)
      3. Platelet count: ≥ 150 × 109/L (100,000 per mm3)
      4. International normalized ratio: ≤ 1.5
    2. Hepatic
      1. Total bilirubin: ≤ 1.5 upper limit normal (ULN) in the absence of Gilbert’s syndrome or ≤ 3 ULN if the patient has Gilbert’s syndrome
      2. ALT and AST: ≤ 1.5 × ULN
    3. Renal
      1. Calculated creatinine clearance Cockcroft-Gault ≥ 45 mL/minute
  8. Provision of signed and dated, written informed consent prior to any study-specific procedures, sampling and analyses.
  9. Age ≥ 18 years at the time of screening.
  10. Eastern Cooperative Oncology Group performance status (ECOG PS: 0-2) with no deterioration over the previous 2 weeks.
  11. Life expectancy ≥ 12 weeks.
  12. Non-sterilized male participants who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to approximately 3 months after the last dose of study intervention.

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. Participants who have received a PARPi.
  2. Known hypersensitivity to dacarbazine or known history of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD9574.
  3. Participants who have received more than one prior line of alkylating chemotherapy regimen.
  4. Participants who had previously experienced Grade 4 hematological toxicities (such as neutropenia or thrombocytopenia) or Grade 3 neutropenia associated with infections, or Grade 3 thrombocytopenia with clinically significant bleeding during prior alkylating chemotherapy.
  5. Participants who have received bevacizumab within the last six months.
  6. Known active or prior hepatitis infection: positive hepatitis C virus HCV) antibody, hepatitis B virus (HBV) surface antigen or HBV core antibody (ant-hoc) at screening.
    1. Participants who have received hepatitis B vaccination, are only anti-HBs positive, and have no clinical signs of hepatitis are eligible.
    2. Participants positive for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  7. Not requiring continuous corticosteroids at a dose of >10mg prednisone per day or equivalent for at least four weeks prior to start of study intervention.

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Investigator(s)

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