PF-06952229 Treatment in Adult Patients With Advanced Solid Tumors
PF-06952229 Treatment in Adult Patients With Advanced Solid Tumors
A Phase 1 dose escalation and expansion study evaluating safety, tolerability and
 pharmacokinetics of PF-06952229 in adult patients with advanced solid tumors.
This is a Phase 1, open label, multi center, multiple dose, dose escalation and expansion,
 safety, tolerability, PK, and pharmacodynamics study of PF 06952229 in previously treated
 patients with advanced or metastatic cancers that may have high TGFbeta signatures and EMT
 expression.

 The study includes Parts 1A and 1B, which are dose-escalation for monotherapy and combination
 therapy with enzalutamide, respectively, and Parts 2A and 2B, which are dose expansion for
 monotherapy and combination therapy with enzalutamide, respectively.
Inclusion Criteria:

 1. For Part 1A: Histological or cytological diagnosis of a solid tumor that is
 advanced/metastatic, patients are intolerant to standard treatment, resistant to
 standard therapy or for which no standard therapy is available for the following tumor
 types:

 Breast cancer; Prostate cancer (mCRPC testosterone less than 50 ng/dL); Squamous cell
 cancer of the head and neck; Melanoma; Mesothelioma; Pancreatic cancer; Colorectal
 cancer; Renal cell carcinoma; Hepatocellular cancer.

 2. For Part 1B, Part 2A, and Part 2B:

 -  Histologically or cytologically confirmed prostate adenocarcinoma metastatic
 disease.

 -  Effective castration with serum testosterone levels 0.5 ng/mL (1.7 nmol/L).

 -  Having received 3 or more cycles of prior docetaxel therapy (before or after
 abiraterone).

 -  Having PD while receiving abiraterone acetate within 12 months of abiraterone
 treatment initiation.

 -  Progressive disease (PD) by:

 1. Progression in measurable disease per RECIST 1.1 criteria. Patient with
 measurable disease must have at least 1 lesion that can be accurately
 measured in at least 1 dimension (longest diameter to be recorded). Each
 lesion must be at least 10 mm when measured by computed tomography (CT) (CT
 scan thickness no greater than 5 mm) or magnetic resonance imaging (MRI).
 Lymph nodes should be greater than or equal to 15 mm in short axis. As
 defined by PCWG2, if lymph node metastasis is the only evidence of
 metastasis, it must be greater than or equal to 20 mm in diameter when
 measured by spiral CT or MRI. Previously irradiated lesions, primary
 prostate lesion, and bone lesions will be considered non-measurable disease,
 or

 2. Appearance of 2 or more new bone lesions (PCWG2). They must be confirmed by
 other imaging modalities (CT; MRI) if ambiguous results, or

 3. Rising PSA defined (PCWG2) as at least 2 consecutive rises in PSA to be
 documented over a reference value (measure 1) taken at least 1 week apart. •
 Prior abiraterone acetate must be stopped at least 2 weeks before study
 treatment.

 3. Patients must have recently obtained archival tumor tissue available for submission to
 the sponsor (except for Part 2A - monotherapy dose expansion). Patients enrolled in
 Part 1 and Part 2 should have access to their archival formalin-fixed
 paraffin-embedded material, collected within 6 months of screening, containing tumor
 that is of diagnostic quality and representative of their diagnosed malignancy or
 whenever possible, consent to undergo a biopsy during screening. The sponsor should be
 contacted if obtaining a new biopsy is not medically feasible for approval to enroll,
 prior to initiating screening activities.

 4. Patients entering the study in the subgroup(s) requiring mandatory pre- and on
 treatment tumor biopsies in Part 2A and 2B must have a tumor amenable to biopsy and
 consent to these planned biopsy procedures. The sponsor should be contacted if
 obtaining a pre-treatment and on treatment biopsies is not medically feasible for
 approval to enroll, prior to initiating screening activities.

 5. Age 18 years or older

 6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.

 7. Adequate bone marrow function (see Appendix 3), including:

 -  Absolute Neutrophil Count (ANC) greater than or equal to 1,500/mm3;

 -  Platelets greater than or equal to 100,000/mm3;

 -  Hemoglobin greater than or equal to 9 g/dL.

 8. Adequate renal function, including serum creatinine less than or equal to 1.5 x upper
 limit of normal (ULN) or estimated creatinine clearance greater than or equal to 60
 mL/min as calculated using the method standard for the institution. In equivocal
 cases, a 24 hour urine collection test can be used to estimate the creatinine
 clearance more accurately. In Part 2: Serum creatinine of less than or equal to 3.0 x
 upper limit of normal.

 9. Adequate liver function, including:

 -  Total serum bilirubin less than or equal to 0.5 x ULN unless the patient has
 documented Gilbert syndrome;

 -  Aspartate and alanine aminotransferase (AST and ALT) less than or equal to 2.5 x
 ULN less than or equal to 5.0 x ULN if there is liver involvement by the tumor;

 -  Alkaline phosphatase less than or equal 2.5 x ULN less than or equal to 5 x ULN
 in case of bone metastasis).

 10. Serum phosphate within normal range (if abnormal, must be nonclinically significant
 per the Investigator and approval for patient inclusion after agreement from sponsor.

 11. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade 1
 except for alopecia and those listed in the specific exclusion criteria.

 12. For Part 1A monotherapy dose escalation: serum pregnancy test (for females of
 childbearing potential) negative at screening.

 13. For Part 1A monotherapy dose escalation: female patients of nonchildbearing potential
 must meet at least 1 of the following criteria:

 -  Achieved postmenopausal status, defined as follows: cessation of regular menses
 for at least 12 consecutive months with no alternative pathological or
 physiological cause; and must have a serum follicle stimulating hormone level
 confirming the postmenopausal state;

 -  Have undergone a documented hysterectomy and/or bilateral oophorectomy;

 -  Have medically confirmed ovarian failure. All other female patients (including
 female patients with tubal ligations) are considered to be of childbearing
 potential.

 14. Evidence of a personally signed and dated informed consent document indicating that
 the patient has been informed of all pertinent aspects of the study.

 15. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
 and other procedures.

 Exclusion Criteria

 Patients with any of the characteristics/conditions listed below will not be included in
 the study:

 Any labs may be repeated for confirmation. Only the lab result requiring confirmation must
 be repeated, not the entire panel.

 1. For Parts 1B, 2A, and 2B:

 -  Prior chemotherapy other than docetaxel for prostate cancer, except estramustine,
 adjuvant/neoadjuvant treatment completed more than 3 years ago;

 -  Less than 28 days elapsed from prior treatment with chemotherapy, immunotherapy,
 radiotherapy, or surgery to the time of study enrollment.

 2. Central Nervous System (CNS) metastases, carcinomatous meningitis, or leptomeningeal
 disease as indicated by baseline brain MRI (or CT with contrast if MRI is medically
 contraindicated), clinical symptoms, cerebral edema, and/or progressive growth. If
 contrast is medically contraindicated, a non-contrast CT scan may be performed.

 3. Patients with a history of CNS metastases or cord compression.

 4. Liver metastases at baseline as evidenced by CT scan or MRI that may be at risk for
 bleeding, such as those that are greater than 1 cm,

 5. Patients with advanced/metastatic, symptomatic, visceral spread, that are at risk of
 life threatening complications in the short term (including patients with massive
 uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and
 over 50% liver involvement). Note: Patients with indwelling catheter for drainage, or
 requirement for drainage no more frequently than monthly will be allowed.

 6. Any other active malignancy within 3 years prior to study entry, except for adequately
 treated basal cell or squamous cell skin cancer, or carcinoma in situ.

 7. Patients with a history of clinically significant tumor bleeding (except for bleeding
 in a post-operative setting), coagulopathy or arterio-venous malformations (AVM) or
 aneurysms in the CNS, liver, lung or other major organ of the body. Patients with
 known Osler-Weber-Rendu disease, Hemophilia A, Hemophilia B (Christmas Disease), Von
 Willibrand's Disease, Factor 13 deficiency and Factor 7 deficiency, antibodies to
 Factors 8 and 7, history of other bleeding diatheses and abnormal INR values.

 8. Evidence of a tumor that compresses or invades major blood vessels or tumor cavitation
 that in the opinion of the investigator is likely to bleed.

 9. Major surgery within 4 weeks prior to first dose.

 10. Prior organ transplantation including heart and allogeneic stem cell transplantation.

 11. Radiation therapy within 4 weeks prior to study entry. Note: Patients who have
 received radiotherapy must have recovered from any reversible side effects, such as
 nausea and vomiting.

 12. Last anti cancer therapy including investigational drug(s) within 28 days (or 5
 half-lives, whichever is shorter) prior to study entry excluding hormonal therapy.

 13. Active and clinically significant bacterial, fungal, or viral infection, including
 known hepatitis B virus (HBV), known hepatitis C virus (HCV), known human
 immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related
 illness. In equivocal cases, with positive serology, those patients with a negative
 viral load are potentially eligible provided the other entry criteria are met. Note:
 Inclusion of patients with well controlled HIV, HBV or HCV can be discussed with
 sponsor on a case by case basis.

 • COVID-19/SARS-CoV2: Refer to Appendix 8 for further information.

 14. Any of the following in the previous 6 months: myocardial infarction, congenital long
 QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular
 tachyarrhythmia and ventricular fibrillation), right bundle branch block and left
 anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery
 bypass graft, symptomatic congestive heart failure (New York Heart Association class
 III or IV), cerebrovascular accident, transient ischemic attack, or symptomatic
 pulmonary embolism; deep venous thrombosis (DVT); arterial occlusive disease; ongoing
 cardiac dysrhythmias of National Cancer Institute (NCI) CTCAE Grade 2 or higher ,
 atrial fibrillation of any grade that is uncontrolled, or QTcF interval greater than
 470 msec at screening. Note: There is an exception where a cardiac rhythm
 device/pacemaker is fitted and results in QTcF greater than 470 msec.

 15. Anticoagulation therapy with heparin, low molecular weight heparin, vitamin K
 antagonists, anti-platelet agents, or factor Xa inhibitors throughout the study and
 for at least 28 days post the last dose of study treatment. (If anticoagulation
 therapy is medically indicated on trial, patients should stop treatment with
 PF-06952229. For those requiring temporary anticoagulant therapy, resumption of
 PF-06952229 treatment may be permitted after discussion with the Sponsor. In any other
 case, study treatment should be permanently discontinued, and the patient should enter
 the follow-up portion of the trial.)

 16. Moderate or severe heart valve function defect including moderate or severe valve
 stenosis or regurgitation.

 17. Evidence or history of septal aneurysm, other heart aneurysm, or any aneurysm of the
 major vessels.

 18. Grade 3 or higher cardiac troponin I at baseline.

 19. Left ventricular ejection fraction (LVEF) of less than or equal to 50% or significant
 valvular regurgitation.

 20. Hypertension that cannot be controlled by medications (greater than 150/90 mmHg
 despite optimal medical therapy) or requiring more than 2 medications for adequate
 control.

 21. Clinically significant non healing or healing wounds.

 22. For patients entering the combination with enzalutamide arm, history of seizures other
 than isolated febrile seizure in childhood.

 23. Has a history of a cerebrovascular accident or transient ischemic attack less than 6
 months ago.

 24. Known or suspected hypersensitivity to active ingredient/excipients of PF 06952229 or
 enzalutamide.

 25. Other acute or chronic medical or psychiatric condition, including recent (within the
 past year) or active suicidal ideation or behavior or laboratory abnormality that may
 increase the risk associated with study participation or investigational product
 administration or may interfere with the interpretation of study results and, in the
 judgment of the investigator, would make the patient inappropriate for entry into this
 study.

 26. Investigator site staff members directly involved in the conduct of the study and
 their family members, site staff members otherwise supervised by the investigator, or
 patients who are Pfizer employees, including their family members, directly involved
 in the conduct of the study.

 27. For Part 1A Monotherapy Dose Escalation: Pregnant female patients; breastfeeding
 female patients; fertile male patients and female patients of childbearing potential
 who are unwilling or unable to use 2 highly effective methods of contraception as
 outlined in this protocol for the duration of the study and for at least 28 days after
 the last dose of investigational product.

 28. For Part 1B Combination Dose Escalation, Part 2A Monotherapy Expansion, and Part 2B
 Combination Dose Expansion: fertile male patients and female partners of childbearing
 potential who are unwilling or unable to use 2 highly effective methods of
 contraception as outlined in this protocol for the duration of the study and for at
 least 28 days after the last dose for monotherapy (Part 2A) or for at least 3 months
 after the last dose for combination therapy (Part 1B and Part 2B).

 29. Inability to consume or absorb study drug, including but not limited to:

 • Active inflammatory gastrointestinal (GI) disease, known diverticular disease or
 previous gastric resection or lap band surgery. Impairment of gastro intestinal
 function or GI disease that may significantly alter the absorption of PF 06952229,
 such as history of GI surgery with may result in intestinal blind loops and patients
 with clinically significant gastroparesis, short bowel syndrome, unresolved nausea,
 vomiting, active inflammatory bowel disease or diarrhea of CTCAE Grade greater than 1.

 30. Current use or anticipated need for food or drugs that are known strong and moderate
 CYP3A4/5 inhibitors, including their administration within 10 days or 5 half lives of
 the CYP3A4/5 inhibitor, whichever is longer, prior to first dose of investigational
 product.

 31. Current use or anticipated need for drugs that are known strong and moderate CYP3A4/5
 inducers, including their administration within 10 days or 5 half lives of the
 CYP3A4/5 inducer, whichever is longer, prior to the first dose of investigational
 product (See Section 5.7).

 32. Have initiated bisphosphonates or approved receptor activator of nuclear factor kappa
 B ligand (RANK L) targeted agents (for example, denosumab) less than 14 days prior to
 study entry, unless there is agreement with the medical monitor.

 33. Active, known suspect suspected autoimmune diseases including inflammatory bowel
 disease (including ulcerative colitis and Crohn's disease), rheumatoid arthritis,
 systemic progressive sclerosis, systemic lupus erythematosus (SLE), autoimmune
 vasculitis (eg, Wegener's Granulomatosis), CNS or motor neuropathy considered to be of
 autoimmune origin (eg, Gullian Barre Syndrome, Myasthenia Gravis, Multiple Sclerosis).