AZD5153 in Patients With Relapsed or Refractory Solid Tumors, Including Lymphomas
Condition: Malignant Solid Tumors; Lymphoma; Ovarian Cancer; Breast Cancer; Pancreatic Cancer; Prostate Cancer
MeSH terms: Lymphoma; Neoplasms; Prostatic Neoplasms; Pancreatic Neoplasms; Ovarian Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      This is a first-time-in-man (FTIM) multicenter, dose escalation study designed to investigate
      the safety, pharmacokinetics, and pharmacodynamics of AZD5153 in patients with malignant
      solid tumors, including lymphomas.
    

Detailed description: 
      The trial will be conducted in two parts, dose escalation and dose expansion. AZD5153 will be
      investigated as a monotherapy and in combination with olaparib.

      AZD5153 monotherapy (dose escalation):

      This part of the study will enroll patients with advanced solid malignancies, including
      lymphoma, and test safety and tolerability of AZD5153 administered as a monotherapy. The dose
      escalation will proceed by two-fold increments or through lower doses suggested by the CRM
      until an MTD as defined by dose-limiting toxicity is reached.

      Single daily (QD) and twice daily (BID) dosing schedules will be explored in the monotherapy
      cohort. Additional dose levels or dosing schedules may be evaluated and recommended by study
      Safety Review Committee (SRC) based on the emerging PK and safety data.

      When the AZD5153 monotherapy MTD is established, an expansion cohort consisting of up to 12
      additional evaluable patients may be enrolled to confirm the safety and tolerability of the
      MTD. The dose expansion will be initiated and will enroll patients with histologically or
      cytologically confirmed platinum resistant or platinum-refractory high grade serous ovarian
      (HGSO) cancer.

      Mandatory tumor biopsies at screening for ovarian cancer patients will be required for
      patient enrollment in the MTD dose expansion cohort. Optional on-treatment biopsies will be
      requested from consenting patients in the ovarian expansion cohort.

      AZD5153 + olaparib combination:

      Dose escalation of AZD5153 in combination with olaparib will also be investigated while the
      AZD5153 monotherapy dose escalation is ongoing and prior to determination of a monotherapy
      MTD.

      The starting dose of AZD5153 in combination with olaparib will be a dose that has been shown
      to be safe and tolerated in monotherapy and has been chosen because clinical exposure
      achieved at this dose is equivalent to preclinical exposure causing tumour growth inhibition
      in animal models. If the starting dose in combination with olaparib is safe and tolerated,
      the dose of AZD5153 will be escalated, using the same method as for the monotherapy part of
      the study, keeping the olaparib dose fixed at 300 mg BID. Intermittent schedules as well as
      continuous BID or QD dosing of AZD5153 in combination with 300 mg BID olaparib might be
      tested until a safe and tolerated combination dose and schedule is determined. However, the
      total dose per cycle of AZD5153 used in combination with olaparib won't exceed the total dose
      per cycle that has been shown to be safe and tolerated as a monotherapy, and won't be higher
      than the dose declared to be the monotherapy MTD. If intermittent dosing is explored then the
      CRM will consider cumulative dosing rather than daily dosing.

      AZD5153 and olaparib will be administered in continuous cycles of 21 days. The combination
      dose escalation part will run in parallel with the AZD5153 monotherapy part (dose escalation
      and expansion) and will continue until a safe and tolerated combination dose of the two
      agents is declared. Mandatory paired tumor biopsies at screening and on-treatment will be
      required for patients enrolled into the combination dose escalation.

      Once a dose and schedule of AZD5153 in combination with olaparib is established, up to 12
      additional evaluable patients might be enrolled to confirm the safety and tolerability of the
      dose and schedule of AZD5153 and olaparib in one or more of the indications where clinical
      activity is observed. Patients with platinum-resistant or platinum-refractory HGSO cancer,
      triple negative breast cancer, metastatic castration resistant prostate cancer, or pancreatic
      ductal adenocarcinoma will be eligible for the expansion cohort.
    

Intervention name(s): AZD5153; Olaparib
Intervention type(s): Drug; Drug
Intervention description(s): AZD5153 is to be taken as oral capsules once or twice per day each day in 21 day cycles. Dosing will continue until disease progression or other study discontinuation criteria are met.; Olaparib, 300 mg, will be taken BID as oral capsules.
Other intervention name(s): Lynparza
Intervention MeSH terms: Olaparib
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: AZD5153; Olaparib; Malignant solid tumors; Lymphoma; Ovarian Cancer; BRD4; Triple negative breast cancer; Pancreatic cancer; Prostate cancer