PRIMARY OBJECTIVE:
I. To estimate the objective radiographic response rate to single agent rogaratinib (BAY
1163877) in two cohorts of patients with sarcoma: Cohort A defined as patients with a sarcoma
which harbors an alteration in fibroblast growth factor receptor (FGFR) 1, 2, 3 or 4
identified by next-generation sequencing profiling, and Cohort B defined as patients with
advanced succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST).
SECONDARY OBJECTIVES:
I. To estimate progression-free survival (PFS) and overall survival (OS) in patients in
Cohort A and Cohort B treated with rogaratinib (BAY 1163877).
II. Further assessment for safety and tolerability.
EXPLORATORY OBJECTIVES:
I. To evaluate serial measurements of FGFR and FGFR ligand in serial tumor biopsies as
potential pharmacodynamic markers of FGFR pathway inhibition by ribonucleic acid sequencing
(RNA-seq) (pre-treatment biopsy and post-progression biopsy).
II. Whole exome sequencing (WES) of the pre and post treatment biopsy to help identify
mechanisms of resistance.
III. To bank tumor material, germline deoxyribonucleic acid (DNA), and peripheral blood for
potential future research for participating subjects who provide additional consent.
OUTLINE:
Patients receive rogaratinib orally (PO) twice daily (BID) on days 1-28. Treatment repeats
every 28 days for up to 24 cycles in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up at 30 days.
Inclusion Criteria:
- Participant must have histologically confirmed sarcoma with FGFR alteration identified
by next-generation sequencing profiling with the exception of SDH-deficient GIST who
can be enrolled regardless of FGFR status. Initial testing can be performed on
archival tissue
- Presence of measurable disease: Patient must have measurable disease
- Patients must have progressed following at least one standard prior chemotherapy
regimen with the exception of SDH-deficient GIST for which there is no standard of
care
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Hemoglobin >= 8.0 g/dL
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =<
3.0 x institutional ULN (unless liver metastases are present in which case it must be
=< 5 x ULN)
- Creatinine =< 1.5 x institutional ULN OR glomerular filtration rate (GFR) >= 60
mL/min/1.73 m^2
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression
- Patients must be disease-free of prior invasive malignancies for > 5 years with the
exception of curatively-treated basal cell or squamous cell carcinoma of the skin or
carcinoma in situ of the cervix
- NOTE: If there is a history of prior malignancy, patients must not be receiving
other specific treatment for that cancer
- Patients should have completed prior treatment for their cancer: chemotherapy or
radiotherapy must have been completed for greater than 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study
- Patients should have recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1) with the exception of alopecia
- Patients with known history or current symptoms of cardiac disease, or history of
treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
function using the New York Heart Association functional classification. To be
eligible for this trial, patients should be class 2B or better
- Participant is willing to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up
- Participant must be able to swallow and maintain pills
- Women of childbearing potential must have a negative urine or serum pregnancy test
within 28 days of initial dose of rogaratinib (BAY 1163877), and again within 7 days
prior to treatment on day 1. If screening occurs within 7 days of day 1, only one
pregnancy test is required. Postmenopausal is defined as:
- Amenorrhoeic for 1 year or more following cessation of exogenous hormonal
treatments
- Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the
post-menopausal range for women under 50
- Radiation-induced oophorectomy with last menses > 1 year ago
- Chemotherapy-induced menopause with > 1-year interval since last menses, or
surgical sterilization (bilateral oophorectomy or hysterectomy)
- The effects of rogaratinib (BAY 1163877) on the developing human fetus are unknown.
For this reason and because kinase inhibitor agents are known to be teratogenic, women
of child-bearing potential and men must agree to use adequate contraception (hormonal
or barrier method of birth control; abstinence) prior to study entry, for the duration
of study participation, and 4 months after completion of rogaratinib (BAY 1163877).
Should a woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately. Men
treated or enrolled on this protocol must also agree to use adequate contraception
prior to the study, for the duration of study participation, and 4 months after
completion of rogaratinib (BAY 1163877) administration
- Ability to understand and the willingness to sign a written informed consent document.
Participants with impaired decision-making capacity (IDMC) who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible
Exclusion Criteria:
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to rogaratinib (BAY 1163877)
- Concomitant administration with sensitive substrates/narrow therapeutic index drugs of
CYP3A4, P-gp BCRP, MATE1, and MATE2K, and strong inhibitors and inducers of CYP3A4
should be avoided. Use caution with strong inhibitors and inducers of P-glycoprotein
(gp). Because the lists of these agents are constantly changing, it is important to
regularly consult a frequently-updated medical reference. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because rogaratinib (BAY 1163877) is
kinase inhibitor agent with the potential for teratogenic or abortifacient effects.
Because there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with rogaratinib (BAY 1163877), breastfeeding
should be discontinued if the mother is treated with rogaratinib (BAY 1163877)
