A Phase II Trial to Evaluate the Efficacy of AZD6094 (HMPL-504) in Patients With Papillary Renal Cell Carcinoma (PRCC)

• Assess progression-free survival (PFS) in patients with PRCC and in the subgroup of MET-positive patients. [ Time Frame: Up to 7 months ]
  Progression-free survival is defined as the time from first dose until the date of objective disease progression or death (by any cause in the absence of progression).
• Assess the safety and tolerability of AZD 6094 [ Time Frame: Up to 7 months ]
  Safety profiles will be assessed in terms of AEs and laboratory data, vital signs and ECGs that will be collected for all patients.
• Pharmacokinetics (PK) of AZD6094 and major metabolites M2 and M3 for AUC, AUC(0-24), AUC(0-t), AUCss, Cmax, Css max, and Css min [ Time Frame: Cycle 1 Day 8 and 15, Cycle 2 Day 1, Cycle 3, Day 1, and Cycle 4, Day 1 ]
  Characterise the pharmacokinetics (PK) of AZD6094 and the major metabolites M2 and M3 following administration to steady state after multiple dosing when given orally.
• Assess duration of response according to RECIST v1.1 [ Time Frame: Up to 7 months ]
  Duration of response is defined as the time from the date of first documented response until the date of documented progression or any cause death. In the case where a subject does not progress following response, the duration of response will be the same as the PFS censoring time.
• Assess duration of overall survival according to RECIST v1.1 [ Time Frame: Up to 7 months ]
  Overall survival (OS) is defined as the time from the date of first treatment until death due to any cause.
• Change from baseline in target lesion tumour size [ Time Frame: 12 weeks ]
  The percentage change from baseline in target lesion tumour size will be measured at 12 weeks.
• Pharmacodynamic (PDc) effects will be assessed by measuring biomarkers phospho-cMET and total-cMET. [ Time Frame: 6 weeks, 12 weeks, at discontinuation of treatment, and at disease progression. ]
  The pharmacodynamic effects of AZD6094 will be evaluated in tumour tissue paired biopsies (a pre-dose tumour biopsy and paired tumour biopsies post-dose). The biomarkers investigated may include, but are not limited to, phospho-cMet and total-cMet.

• Assess progression free survival [ Time Frame: Up to 7 months ]
  Progression-free survival is defined as the time from randomisation until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the subject withdraws from randomised therapy or receives another anti-cancer therapy prior to progression.
• Assess the safety and tolerability of AZD 6094 [ Time Frame: Up to 7 months ]
  Safety profiles will be assessed in terms of AEs and laboratory data, vital signs and ECGs that will be collected for all patients.
• Pharmacokinetics (PK) of AZD6094 and major metabolites M2 and M3 for AUC, AUC(0-24), AUC(0-t), AUCss, Cmax, Css max, and Css min [ Time Frame: Cycle 1 Day 8 and 15, Cycle 2 Day 1, Cycle 3, Day 1, and Cycle 4, Day 1 ]
  Characterise the pharmacokinetics (PK) of AZD6094 and the major metabolites M2 and M3 following administration to steady state after multiple dosing when given orally.
• Assess change in target lesion tumor size from baseline [ Time Frame: Up to 7 months ]
  Change in Target Lesion is percentage change from baseline in tumor size at 12 weeks. This is based on RECIST target lesion measurements taken at baseline and at week 12. Target lesions are measureable tumour lesions.
• Assess duration of response according to RECIST v1.1 [ Time Frame: Up to 7 months ]
  Duration of response is defined as the time from the date of first documented response until the date of documented progression or any cause death. In the case where a subject does not progress following response, the duration of response will be the same as the PFS censoring time.
• Assess duration of overall survival according to RECIST v1.1 [ Time Frame: Up to 7 months ]
  Overall Survival (OS) - Overall survival is defined as the time from the date of randomization until death due to any cause.

This is an open-label, single-arm, multicentre, global, phase II study designed to evaluate the efficacy and safety of AZD6094 in patients with papillary renal cell carcinoma (PRCC) who are treatment naïve or previously treated.

An independent central pathology review of tumour samples will be used to confirm the diagnosis of PRCC of all patients enrolling. However, locally available pathology results confirming PRCC will be allowed for timely study entry.

The study will comprise two stages. In Stage 1 approximately 20 patients will be enrolled. This group is considered sufficient to provide preliminary assessment of the anti-tumour activity of AZD6094 in the form of non-binding futility analysis.

If ≤ 2 tumour responses are observed in the first 20 evaluable patients termination of the study will be considered taking into account the relevant molecular profile of the patients and additional information from related studies in the drug development programme.

All patients entering the study will take AZD6094 600 mg by mouth (PO) once daily (QD). Treatment will be given continuously.

Following the baseline assessment, efficacy will be assessed by objective tumour assessments every 6 weeks (±7 days), for the first 12 months and every 12 weeks thereafter until objective disease progression as defined by RECIST v1.1 There will be a data cut-off after all patients have completed at least 12 weeks of treatment with AZD6094 or withdrawn. The database will be locked and data analysis will be performed on this dataset.

Any patients still receiving study drug at the time of data cut-off will be able to continue to receive AZD6094 while deriving clinical benefit. Such patients will continue to be monitored for the occurrence of serious adverse events up to 28 days after the last dose of AZD6094.

After database lock (DBL) tumour assessments will be performed every 12 weeks (±7 days) until objective disease progression as defined by RECIST v1.1.

Patients discontinuing treatment due to documented disease progression will enter a survival follow-up period, where they will be followed for the initiation of subsequent anti-cancer therapies every 3 months until death, loss to follow-up or withdrawal of consent, whichever comes first.

Patients discontinuing treatment prior to documented disease progression will enter a progression-free survival follow-up period where they will continue to have disease assessments every 6 weeks (±7 days) for the first 12 months of follow-up and every 12 weeks thereafter until objective disease progression as defined by RECIST v1.1, death, loss to follow-up or withdrawal of consent, whichever comes first. After DBL, tumour assessments will be performed in the progression free survival patient population every 12 weeks (±7 days) until objective disease progression as defined by RECIST v1.1

Inclusion criteria

1. Provision of informed consent prior to any study specific procedures, sampling and analyses.
2. Histologically confirmed papillary renal cell cancer, which is locally advanced or metastatic.
3. Availability of an archival tumor sample or a pre-treatment fresh tumor sample for confirmation of PRCC by a central laboratory and other biomarker
4. Treatment naïve or have failed on previous treatment for PRCC. Previous treatments may include: targeted therapy (i.e. sunitinib, sorafenib, bevacizumab, pazopanib, temsirolimus, and everolimus), traditional immunotherapy (i.e. interferon-a, Interleukin-2), chemotherapy or a combination of chemoimmunotherapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. At least one lesion, not previously irradiated, and not chosen for a biopsy if performed during the screening period that can be accurately measured at baseline and which is suitable for accurate repeated measurements.

7. Adequate hematological function defined as:

   1. (ANC) ≥1500/μL
   2. (Hgb) ≥9 g/dL
   3. Platelets ≥100,000/μL

8. Adequate liver function defined as:

   1. ALT and AST ≤2.5 x the upper limit of normal (ULN)
   2. Total bilirubin ≤1.5 x ULN
9. Adequate renal function defined as glomerular filtration rate (GFR) ≥ 40 mL/min,
10. Adequate coagulation parameters, defined as International Normalisation Ratio(INR) <1.5 x ULN or activated partial thromboplastin time (aPTT) <1.5 x ULN.
11. Patients with known tumor thrombus or deep vein thrombosis (DVT) are eligible if stable on low molecular weight heparin (LMWH) for ≥4 weeks.
12. Females should be using adequate contraceptive measures should notbe breast feeding, and must have a negative pregnancy test prior to start of dosing ifof childbearing potential or must have evidence of non-childbearing potential
13. Male patients should be willing to use barrier contraception, i.e. condoms.
14. Ability to swallow and retain oral medications.
15. Predicted life expectancy ≥12 weeks.
16. Aged at least 18 years.
17. Willingness and ability to comply with study and follow-up procedures.
18. Ability to understand the nature of this study and give written informed consent.

Exclusion criteria

1. Most recent chemotherapy, immunotherapy, chemo-immunotherapy, or investigational agents <21 days of the first dose of study treatment. Most recent targeted therapy <14 days of the first dose of study treatment.
2. Unresolved toxicities from any prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment with the exception of alopecia.
3. Prior or current treatment with a cMet inhibitor
4. Strong inducers or inhibitors of CYP3A4, strong inhibitors of CYP1A2, or CYP3A4 substrates with a narrow therapeutic range within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort)
5. Wide field radiotherapy (including therapeutic radioisotopes such as strontium-89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy
6. Major surgical procedures ≤28 days of beginning study drug or minor surgical procedures ≤7 days. No waiting is required following port-a-cath placement.
7. Previously untreated brain metastases.
8. Current leptomeningeal metastases or spinal cord compression due to disease.
9. Acute or chronic liver or pancreatic disease.
10. Uncontrolled diabetes mellitus.
11. Gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy

12. Any of the following cardiac diseases currently or within the last 6 months:

    1. Unstable angina pectoris
    2. Congestive heart failure (New York Heart Association [NYHA] ≥ Grade 2
    3. Acute myocardial infarction
    4. Stroke or transient ischemic attack
13. Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] >160 mmHg or diastolic blood pressure (DBP) >100 mmHg) (patients with values above these levels must have their blood pressure (BP) controlled with medication prior to starting treatment).
14. Mean resting correct QT interval (QTc) >470 msec obtained from triplicate ECGs.
15. Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiograms (ECGs), e.g. complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec.
16. Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital or familial long QT syndrome or family history of unexplained sudden death under 40 years of age or any concomitant medications known to prolong QT interval.
17. Currently receiving treatment with therapeutic doses of warfarin sodium. Low molecular weight heparin (LMWH) is allowed.
18. Serious active infection at the time of treatment, or another serious underlying medical condition that would impair the ability of the patient to receive protocol treatment.
19. Known diagnosis of human immunodeficiency virus (HIV), hepatitis B, or hepatitis C.
20. Presence of other active cancers, or history of treatment for invasive cancer ≤5years. Patients with Stage I cancer who have received definitive local treatment at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e., non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.
21. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.