A Phase II Trial to Evaluate the Efficacy of AZD6094 (HMPL-504) in Patients With Papillary Renal Cell Carcinoma (PRCC)
Condition: Papillary Renal Cell Cancer
MeSH terms: Carcinoma, Renal Cell
Intervention: AZD6094
Intervention description: AZD6094 is a potent and selective small molecule mesenchymal epithelial transition (c-MET) kinase inhibitor.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 111.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: AZD6094; Savolitinib; Papillary Renal Cell Cancer

Summary:

      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.
    

Eligibility criteria:

        Inclusion criteria

          1. Provision of informed consent prior to any study specific procedures, sampling and
             analyses.

          2. Histologically confirmed PRCC, 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. Absolute neutrophil count ≥1500/μL

               2. Haemoglobin ≥9 g/dL

               3. Platelets ≥100,000/μL

          8. Adequate liver function defined as:

               1. Alanine aminotransferase and aspartate aminotransferase ≤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 ≥ 40 mL/min,

         10. Adequate coagulation parameters, defined as International Normalisation Ratio <1.5 x
             ULN or activated partial thromboplastin time <1.5 x ULN.

         11. Patients with known tumor thrombus or deep vein thrombosis are eligible if stable on
             low molecular weight heparin for ≥4 weeks.

         12. Females should be using adequate contraceptive measures should not be breast feeding,
             and must have a negative pregnancy test prior to start of dosing if of 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 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 cytochrome P450 3A4 (CYP3A4), strong inhibitors of
             cytochrome P450 1A2 (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 ≥ Grade 2)

               3. Acute myocardial infarction

               4. Stroke or transient ischemic attack

         13. Inadequately controlled hypertension (i.e., systolic blood pressure >160 mmHg or
             diastolic blood pressure >100 mmHg) (patients with values above these levels must have
             their blood pressure controlled with medication prior to starting treatment).

         14. Mean resting correct QT interval (QTc) >470 msec obtained from triplicate
             electrocardiagrams

         15. Any clinically important abnormalities in rhythm, conduction or morphology of resting
             electrocardiograms, 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 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, 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.