Clinical Trials /

PF-06952229 Treatment in Adult Patients With Advanced Solid Tumors

NCT03685591

Description:

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

Related Conditions:
  • Breast Carcinoma
  • Malignant Solid Tumor
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: PF-06952229 Treatment in Adult Patients With Advanced Solid Tumors
  • Official Title: A Phase 1 Dose Escalation Study Evaluating Safety, Tolerability And Pharmacokinetics Of Pf-06952229 In Adult Patients With Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: C3881001
  • NCT ID: NCT03685591

Conditions

  • Hormone Receptor Positive Advanced Breast Cancer
  • Metastatic Breast Cancer
  • Human Epidermal Receptor 2 Negative Advanced Breast Cancer
  • Castration Resistant Prostate Cancer

Interventions

DrugSynonymsArms
PF-06952229Dose Level 1
PalbociclibBreast Cancer (Part 2)
LetrozoleBreast Cancer (Part 2)
EnzalutamideProstate Cancer Part 2

Purpose

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).
    

Trial Arms

NameTypeDescriptionInterventions
Dose Level 1ExperimentalPF-06952229 at 20mg twice daily (BID)
  • PF-06952229
Dose Level 2ExperimentalPF-06952229 at 40 mg BID
  • PF-06952229
Dose Level 3ExperimentalPF-06952229 at 80 mg BID
  • PF-06952229
Dose Level 4ExperimentalPF-06952229 at 150 mg BID
  • PF-06952229
Dose Level 5ExperimentalPF-06952229 at 250 mg BID
  • PF-06952229
Dose Level 6ExperimentalPF-06952229 at 375 mg BID
  • PF-06952229
Dose Level 7ExperimentalPF-06952229 at 500 mg BID
  • PF-06952229
Dose Level 8ExperimentalPF-06952229 at 625 mg BID
  • PF-06952229
Breast Cancer (Part 2)ExperimentalPF-06952229 at recommended part 2 dose (RP2D) in combination with palbociclib and letrozole
  • Palbociclib
  • Letrozole
Prostate Cancer Part 2ExperimentalPF-06952229 at recommended part 2 dose (RP2D) in combination with enzalutamide
  • Enzalutamide

Eligibility Criteria

        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).
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of patients with dose limiting toxicities to determine maximum tolerated dose/recommended Phase 2 dose
Time Frame:Baseline up to 90 days
Safety Issue:
Description:First cycle DLTs will be utilized to determine the max tolerated dose and future escalations or deescalations. A DLT is any of the predefined set of unacceptable adverse events observed and at least possibly related to investigational agents.

Secondary Outcome Measures

Measure:Pharmacokinetic Parameters: Maximum Observed Plasma Concentration (Cmax) as a single agent in Part 1 and in combination in Part 2
Time Frame:Cycle 1 Day 1, Day 7 and Cycle 2 Day 1, Predose, 0.5, 1, 2, 4, 6 hours post dose, pre dose on Cycle 1 Day 15, Cycle 2 Day 7, and Cycle 3 and higher Day 7, and End of Treatment
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Maximum Observed Plasma Concentration (Cmax).
Measure:Pharmacokinetic Parameters: Time to Reach Maximum Observed Plasma Concentration (Tmax)
Time Frame:Cycle 1 Day 1, Day 7 and Cycle 2 Day 1, Predose, 0.5, 1, 2, 4, 6 hours post dose, pre dose on Cycle 1 Day 15, Cycle 2 Day 7, and Cycle 3 and higher Day 7, and End of Treatment
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Time to Reach Maximum Observed Plasma Concentration (Tmax).
Measure:Pharmacokinetic Parameters: Area Under the Curve (AUC)
Time Frame:Cycle 1 Day 1, Day 7 and Cycle 2 Day 1, Predose, 0.5, 1, 2, 4, 6 hours post dose, pre dose on Cycle 1 Day 15, Cycle 2 Day 7, and Cycle 3 and higher Day 7, and End of Treatment
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Area Under the Curve (AUC).
Measure:Pharmacokinetic Parameters: Apparent Oral Clearance (CL/F)
Time Frame:Cycle 1 Day 1, Day 7 and Cycle 2 Day 1, Predose, 0.5, 1, 2, 4, 6 hours post dose, pre dose on Cycle 1 Day 15, Cycle 2 Day 7, and Cycle 3 and higher Day 7, and End of Treatment
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Apparent Oral Clearance (CL/F). Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Measure:Pharmacokinetic Parameters: Apparent Volume of Distribution (Vz/F)
Time Frame:Cycle 1 Day 1, Day 7 and Cycle 2 Day 1, Predose, 0.5, 1, 2, 4, 6 hours post dose, pre dose on Cycle 1 Day 15, Cycle 2 Day 7, and Cycle 3 and higher Day 7, and End of Treatment
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Apparent Volume of Distribution (Vz/F). Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Measure:Pharmacokinetic Parameters: Plasma Decay Half-Life (t1/2)
Time Frame:Cycle 1 Day 1, Day 7 and Cycle 2 Day 1, Predose, 0.5, 1, 2, 4, 6 hours post dose, pre dose on Cycle 1 Day 15, Cycle 2 Day 7, and Cycle 3 and higher Day 7, and End of Treatment
Safety Issue:
Description:Single dose and multiple dose PK will be calculated as data permits including Plasma Decay Half-Life (t1/2). Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Measure:Evaluate preliminary anti-tumor activity of PF-06952229
Time Frame:Baseline and every 8 to 12 weeks through time of confirmed disease progression, unacceptable toxicity, or through study completion, approximately 2 years.
Safety Issue:
Description:Response endpoints based on Response Evaluation Criteria in Solid Tumors 1.1 for solid tumors including HR+ HER2 negative Breast Cancer and Prostate Working Group 3 for Castration Resistant Prostate Cancer.
Measure:Objective Response Rate (ORR)
Time Frame:Baseline up to approximately 2 years
Safety Issue:
Description:Proportion of patients with a reduction in tumor burden as defined by RECIST 1.1. and PWG3 response criteria.
Measure:Duration of Response (DOR)
Time Frame:Baseline up to approximately 2 years
Safety Issue:
Description:Time of initial response until documented tumor progression.
Measure:Progression free survival (PFS)
Time Frame:Baseline up to approximately 2 years
Safety Issue:
Description:The time from Cycle 1 Day 1 dose administration to disease progression or death from any cause.
Measure:Overall Survival (OS)
Time Frame:Baseline up to approximately 2 years
Safety Issue:
Description:Time from Cycle 1 Day 1 until death from any cause.
Measure:Time to Progression (TTP)
Time Frame:Baseline up to approximately 2 years
Safety Issue:
Description:Time from Cycle 1 Day 1 until objective tumor progression.
Measure:Time to Response (TTR)
Time Frame:Baseline up to approximately 2 years
Safety Issue:
Description:Time from Cycle 1 Day 1 to objective tumor response.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Pfizer

Trial Keywords

  • efficacy
  • safety
  • pharmacokinetics
  • dose escalation
  • dose expansion
  • open-label
  • TGFb
  • transforming growth factor beta
  • breast cancer
  • prostate cancer
  • HR+
  • HER2 negative
  • CRPC
  • metastatic
  • advanced
  • adenocarcinoma

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