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Pemigatinib before Surgery for the Treatment of Recurrent Low- or Intermediate Risk Non-Muscle Invasive Bladder Cancer

Trial Status: Active

This phase II trial studies how well pemigatinib before surgery works in treating patients with low- or intermediate risk non-muscle invasive bladder cancer that has come back (recurrent). Fibroblast growth factor receptor (FGFR) genes are genes that, when altered, can lead to and promote the growth of cancer in patients. In non-muscle invasive bladder cancer, FGFR3 gene mutations have been seen in patients with recurrent bladder tumors and a prior history of low or intermediate risk tumors. Pemigatinib is an orally administered drug that inhibits fibroblast growth factor receptors 1, 2, and 3 (FGFR 1 / 2 / 3). Pemigatinib followed by surgery may be an effective treatment in patients with low- and intermediate risk non-muscle invasive bladder cancer.

Inclusion Criteria

  • Prior histologically confirmed low- or intermediate-risk non-muscle invasive urothelial carcinoma of the bladder (NMIBC) defined by: * Low-risk group: Initial tumor with all of the following: ** Solitary tumor ** Ta tumor ** Low-grade ** < 3 cm ** No carcinoma in situ (CIS) * Intermediate-risk group: ** All tumors not defined in the two adjacent categories (between the category of low- and high-risk) * High-risk group: Any of the following: ** T1 tumor ** High-grade ** CIS ** Multiple and recurrent and large ( > 3 cm) Ta low-grade tumors (all conditions must be met for this point on Ta low-grade tumors)
  • Documented tumor recurrence as noted in standard of care follow up cystoscopy
  • Eastern Cooperative Oncology Group (ECOG) (World Health Organization [WHO]) performance status 0-2
  • White blood cell count (WBC) >= 3.0 K/mm^3
  • Absolute neutrophil count (ANC) >= 1.5 K/mm^3
  • Platelets >= 100 K/mm^3
  • Hemoglobin (Hgb) >= 9 g/dL
  • Serum total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 3.0 x ULN
  • Serum calcium =< ULN
  • Serum phosphate =< ULN
  • Serum creatinine =< 1.5 x ULN or serum creatinine > 1.5 – 3 x ULN if calculated creatinine clearance (CrCl) is >= 30 mL/min using the modified Cockcroft-Gault equation
  • Patients who give a written informed consent obtained according to local guidelines

Exclusion Criteria

  • Patients with concurrent upper urinary tract (i.e. ureter, renal pelvis) high-grade urothelial carcinoma of any T-stage * NOTE: Patients with histologically confirmed concurrent upper urinary tract non-invasive low-grade urothelial carcinoma may be considered for enrollment after consultation with the study chair
  • Patients with high grade urothelial carcinoma on their most recent urine cytology
  • Patients with another active second malignancy other than non-melanoma skin cancers and biochemical relapsed prostate cancer. Patients that have completed all necessary therapy and are considered to be at less than 30% risk of relapse are not considered to have an active second malignancy and are eligible for enrollment
  • Patients who have received the last administration of an anti-cancer therapy including chemotherapy, immunotherapy, and monoclonal antibodies =< 4 weeks prior to starting study drug, or who have not recovered from the side effects of such therapy
  • Patients who have received prior selective fibroblast growth factor receptor targeting agents (i.e. pemigatinib, dovitinib, BGJ398, AZD4547, JNJ-42756493, etc.)
  • Patients who have had radiotherapy =< 4 weeks prior to starting study drug, or who have not recovered from radiotherapy toxicities
  • Patients who have undergone major surgery (e.g. intra-thoracic, intra-abdominal or intra-pelvic), open biopsy or significant traumatic injury =< 4 weeks prior to starting study drug, or patients who have had minor procedures (i.e. TURBT), percutaneous biopsies or placement of vascular access device =< 1 week prior to starting study drug, or who have not recovered from side effects of such procedure or injury
  • Patients with any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: * Clinically significant cardiac diseases, including any of the following: ** History or presence of serious uncontrolled ventricular arrhythmias ** Clinically significant resting bradycardia ** Any of the following within 6 months prior to starting study drug: myocardial infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), congestive heart failure (CHF), cerebrovascular accident (CVA), transient ischemic attack (TIA), pulmonary embolism (PE) ** Uncontrolled hypertension defined by a systolic blood pressure (SBP) >= 160 mm Hg and/or diastolic blood pressure (DBP) >= 100 mm Hg, with or without anti-hypertensive medication(s) * Active impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of pemigatinib (e.g. ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection) * Cirrhosis, chronic active hepatitis or chronic persistent hepatitis * Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not mandatory) * Patients who are currently receiving anti-coagulation treatment with therapeutic doses of warfarin. Full-dose anti-coagulation with low molecular weight heparin is permitted. * Patients with a prior history of significant ocular pathology including but not limited to detached retina, retinal vein/artery occlusion, macular degeneration, or glaucoma. Patients with prior history of cataracts are permitted to enroll. * Other concurrent severe and/or uncontrolled concomitant medical conditions (e.g. active or uncontrolled infection, uncontrolled diabetes) that could cause unacceptable safety risks or compromise compliance with the protocol * History of calcium and phosphate hemostasis disorder or systemic mineral imbalance with ectopic calcification of soft tissues (exception: commonly observed calcifications in soft tissues such as the skin, kidney tendon or vessels due to injury, disease, or aging in the absence of systemic mineral imbalance)
  • Pregnant or breast-feeding women
  • Women of child-bearing potential, who are biologically able to conceive, not employing two forms of highly effective contraception. Highly effective contraception must be used throughout the trial and up to 8 weeks after the last dose of study drug (e.g. male condom with spermicidal; diaphragm with spermicide; intra-uterine device). Women of child-bearing potential, defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test =< 14 days prior to starting study drug
  • Fertile males not willing to use contraception, as stated above
  • Patients unwilling or unable to comply with the protocol

Maryland

Baltimore
Johns Hopkins University / Sidney Kimmel Cancer Center
Status: ACTIVE
Contact: Noah M. Hahn
Phone: 443-287-0553

PRIMARY OBJECTIVE:

I. Assess the complete response rate of pemigatinib therapy in patients with recurrent bladder tumors and a prior history of histologically confirmed low- or intermediate-risk non-muscle invasive urothelial carcinoma of the bladder (NMIBC).

SECONDARY OBJECTIVES:

I. Characterize the safety profile of pemigatinib therapy in patients with recurrent bladder tumors and a prior history of histologically confirmed low- or intermediate-risk NMIBC.

II. Assess associations between complete response rate and tumor mutation/fusion status (e.g. FGFR3 specifically, others will also be examined).

III. Assess associations between complete response rate and baseline NMIBC risk group (low- vs. intermediate-risk).

IV. Assess pemigatinib urothelial tissue concentrations as measured within urothelial tissue sampled at post-treatment transurethral resection of bladder tumor (TURBT).

V. Assess 6- 12- and 24-month relapse free survival (RFS) in patients achieving a complete response at initial post-treatment TURBT.

EXPLORATORY OBJECTIVES:

I. Assess associations between complete response rate and tumor intrinsic molecular subtypes (e.g. basal vs. luminal).

II. Assess associations between complete response rate and tumor baseline CD8+ tumor infiltrating lymphocyte density.

III. Assess associations between complete response rate and changes in peripheral blood T-cell clonality as measured at baseline and post-treatment.

IV. Assess the post-treatment effects of pemigatinib on tumor gene expression by ribonucleic acid (RNA) sequencing among patients with residual tumor present at post-treatment TURBT.

V Assess the post-treatment immunomodulatory effects of pemigatinib on the tumor microenvironment as assessed by comparison of pre- and post-treatment immunohistochemistry (IHC) staining for PD-L1, CD8+, FOXP3, phosphorylated (p)FGFR3, and other targets of interest where adequate tissue permits.

VI. Assess associations between the development of hyperphosphatemia and complete response rate.

OUTLINE:

Patients receive pemigatinib orally (PO) once daily (QD) for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients then undergo TURBT. Patients who achieve a complete response at post-treatment TURBT evaluation may receive pemigatinib PO QD on days 1-28. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 6 months for up to 2 years.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Johns Hopkins University / Sidney Kimmel Cancer Center

Principal Investigator
Noah M. Hahn

  • Primary ID J18158
  • Secondary IDs NCI-2019-08582, IRB00182038, CRMS-70663
  • Clinicaltrials.gov ID NCT03914794