Patient case: 45-year-old female with cervical cancer; genetic feature: ERBB2 (S310Y)

Clinical trial: PF-06952229 Treatment in Adult Patients With Advanced Solid Tumors

Summary: A Phase 1 dose escalation study evaluating safety, tolerability and pharmacokinetics of PF-06952229 in adult patients with advanced solid tumors.

Detailed description: 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 cancer that is known to have high TGFbeta signatures and EMT expression.
  This trial includes 2 parts. Part 1 is a a monotherapy dose escalation phase and Part 2 arms A and B is the dose escalation expansion phase. Part 2 Arm A combines PF-06952229 with palbociclib and letrozole in HR+HER advanced or metastatic breast cancer. Part 2 Arm B combines PF-06952229 with enzalutamide in castration resistant prostate cancer (CRPC).

Eligibility: Inclusion Criteria:
  -  Part 1: Histological or cytological diagnosis of a solid tumor that is advanced/metastatic, patients intolerant to standard treatment, resistant to standard therapy or for which no standard therapy is available.
  -  Part 2: Arm A: Patients with histological or cytological proven diagnosis of adenocarcinoma of the breast (HR+ HER2 ) with evidence of either locally advanced disease not amenable to resection or radiation therapy with curative intent or metastatic disease not amenable to curative therapy.
  -  Documentation of HR positive (ie, ER positive and/or progesterone receptor positive tumor, (>1% positive stained cells) and HER2 negative tumor (described above);
  -  Have progressed on prior CDK4/6 inhibitor therapy;
  -  Received greater than or equal to 2 prior lines of therapy in the metastatic setting;
  -  Must have evaluable disease by RECIST v 1.1.
  -  Arm B: Histological or cytological diagnosis of castration resistant prostate cancer (serum testosterone of less than 50 ng/dL). Received either abiraterone and/or enzalutamide treatment and has evidence of prostate cancer progression (per Prostate Cancer Working Group 3 Criteria for progression at trial entry): Elevated prostate specific antigen (PSA) only; Bone only metastasis and nodal disease (Escalation only); Nodal disease (no bone disease present);Visceral (lung, liver, adrenal, CNS) disease (other sites) (For Expansion measurable by RECIST 1.1 only).
  -  Age greater than or equal to 18 years.
  -  Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
  -  Adequate bone marrow function, including: Absolute Neutrophil Count (ANC) greater than or equal to 1,500/mm3 or 1.5 x 109/L; Platelets greater than or equal to 100,000/mm3 or 100 x 109/L; Hemoglobin greater than or equal to 9 g/dL.
  -  Adequate renal function, including serum creatinine less than or equal to1.5 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.
  -  Adequate liver function, including: Total serum bilirubin less than or equal to 1.5 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, 5.0 x ULN if there is liver involvement by the tumor; Alkaline phosphatase less than or equal to 2.5 x ULN (less than or equal to 5 x ULN in case of bone metastasis).
  -  Serum phosphate within normal range (if abnormal, must be not clinically significant per the Investigator and approval for patient inclusion after agreement from sponsor.
  -  Resolved acute effects of any prior therapy to baseline severity or CTCAE less than or equal to Grade 1 except for adverse events not constituting a safety risk by investigator judgment.
  -  Serum pregnancy test (for females of childbearing potential) negative at screening.
  -  Female patients of non-childbearing 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 (FSH) 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.
  -  Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
  -  Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.
  Exclusion Criteria:
  -  Known active uncontrolled or symptomatic Central Nervous System (CNS) metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Patients with a history of CNS metastases or cord compression are eligible if they have been definitively treated (eg, radiotherapy, stereotactic surgery), have discontinued corticosteroid treatment (except for adrenal replacement therapy) for these metastasis for at least 4 weeks, and are clinically stable for 3 months (requires MRI confirmation) with no evidence of progression at time of study enrollment.
  -  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.
  -  Any other active malignancy within 3 years prior to randomization, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ.
  -  Major surgery within 4 weeks prior to first dose.
  -  Prior organ transplantation including heart and allogeneic stem cell transplantation.
  -  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.
  -  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 which requires no treatment free interval.
  -  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.
  -  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; arterial occlusive disease; ongoing cardiac dysrhythmias of National Cancer Institute (NCI) CTCAE Grade greater than or equal to 2, atrial fibrillation of any grade that is uncontrolled, or QTcF interval >470 msec at screening. Note: There is an exception where a cardiac rhythm device/pacemaker is fitted and results in QTcF >470 msec. Anticoagulation (heparin only, no vitamin K antagonists or factor Xa inhibitors) can be allowed if indicated).
  -  Moderate or severe heart valve function defect including moderate or severe valve stenosis or regurgitation.
  -  Evidence or history of septal aneurysm, other heart aneurysm, or any aneurysm of the major vessels.
  -  Grade 3 or greater cardiac troponin I at baseline.
  -  Left ventricular ejection fraction (LVEF) of less than or equal to 50% or significant valvular regurgitation.
  -  Hypertension that cannot be controlled by medications (>150/90 mmHg despite optimal medical therapy) or requiring more than 2 medications for adequate control.
  -  Clinically significant non healing or healing wounds.
  -  For patients entering the combination with enzalutamide arm, history of seizures other than isolated febrile seizure in childhood;
  -  Has a history of a cerebrovascular accident or transient ischemic attack less than 6 months ago.
  -  Known or suspected hypersensitivity to active ingredient/excipients of PF-06952229, letrozole, palbociclib, or enzalutamide.
  -  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.
  -  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.
  -  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.
  -  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 >1.
  -  Current use or anticipated need for food or drugs that are known strong CYP3A4/5 inhibitors, including their administration within 5 half lives of the CYP3A4/5 inhibitor, prior to first dose of investigational product. Current or anticipated use of moderate CYP3A4/5 inhibitors (including their administration within 5 half lives of the CYP3A4/5 inhibitor, prior to first dose of investigational product) should be avoided if possible, and any use will need to be reviewed and approved by the sponsor.
  -  Strong CYP3A4/5 inhibitors: eg, grapefruit juice or grapefruit/grapefruit related citrus fruits (eg, Seville oranges, pomelos), ketoconazole, miconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, indinavir, saquinavir, ritonavir, nelfinavir, amprenavir, fosamprenavir nefazodone, lopinavir, troleandomycin, mibefradil, and conivaptan. Current list can be found at Indiana University Purdue University Indianapolis.
  -  Moderate CYP3A4/5 inhibitors: eg, erythromycin, verapamil, atazanavir, delavirdine, fluconazole, darunavir, diltiazem, aprepitant, imatinib, tofisopam, ciprofloxacin, and cimetidine. Current list can be found at Indiana University Purdue University Indianapolis.
  -  Current use or anticipated need for drugs that are known strong CYP3A4/5 inducers, with the exception of enzalutamide in Part 2, including their administration within 4 weeks or 5 half lives of the CYP3A4/5 inducer, whichever is longer, prior to the first dose of investigational product. Strong CYP3A4/5 inducers: eg, phenobarbital, rifampin, phenytoin, carbamazepine, rifabutin, rifapentine, clevidipine, St. John's Wort.
  -  Have initiated bisphosphonates or approved receptor activator of nuclear factor kappa B ligand (RANK L) targeted agents (for example, denosumab) <14 days prior to randomization.
  -  Active, known or 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, Guillain-Barre Syndrome, Myasthenia Gravis, Multiple Sclerosis).

Relevance to patient case: not relevant