Multi-arm, Non-randomized, Open-Label Phase IB Study to Evaluate GSK3052230 in Combination With Paclitaxel and Carboplatin, or Docetaxel or as Single Agent in Subjects With Solid Malignancies and Deregulated FGF Pathway Signaling
- Signed written informed consent
- Histologically or cytologically confirmed diagnosis: Arm A and B- stage IV squamous
NSCLC with Fibroblast growth factor receptor 1 (FGFR1) gene amplification by central
laboratory testing. Arm C- advanced solid tumor with deregulated FGF pathway
signaling, for which all lines of standard therapies have been exhausted or for which
no standard treatment is available.
For specific arms the following requirements:
Arm A: Subjects who have received no prior therapy for Stage IV disease. Arm B: Subjects
who have documented tumor progression (based on radiological imaging) or intolerability
after receiving only one prior line of platinum containing combination chemotherapy for
Stage IV disease..
Arm C: Subjects who have exhausted all lines of standard therapies or for whom there is no
standard treatment for the specific tumor.
- Availability of archival tumor tissue required for assessment of deregulated FGF
pathway signaling e.g. FGFR1 amplification, provided no systemic therapy has been
given since the biopsy was obtained. If archival tissue is not available, a fresh
biopsy is required. In Arms A and B, subjects will be prospectively screened for
FGFR1 gene amplification using a Fluorescence in situ hybridization (FISH) assay. For
inclusion in this study, an evidence of gene amplification or increased copy number
will be required. FGFR1 gene amplification will determined by central laboratory
- Measurable disease per RECIST version 1.1
- Male or female >=18 years of age.
- Women of childbearing potential must have a negative serum pregnancy test within 7
days of first dose of study treatment and agree to use effective contraception during
the study and for 21 days following the last dose of study treatment.
- For Arms A and B: Men with a female partner of childbearing potential must have
either had a prior vasectomy or agree to use effective contraception for at least 2
weeks prior to administration of the first dose of study treatment [and for at least
4 weeks after the last dose of chemotherapy given in this study] to allow for
clearance of any altered sperm. Arm C: No male contraception restrictions
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 for Arm A
subjects and 0-2 for Arms B and C
- French subjects: In France, a subject will be eligible for inclusion in this study
only if either affiliated to or a beneficiary of a social security category
- Must have adequate organ function as defined by the following baseline values:
Absolute neutrophil count >=1.5 x 109/Liter, Hemoglobin >=10 gram (g)/decilitre(dL),
Platelets >=100 x 109/L, Partial thromboplastin time (PTT) <=1.25 x upper limit of
normal (ULN), Albumin >=2.5 g/dL, Serum bilirubin <=1.25 times ULN (for Arm B: <=ULN
), Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) <=2.5 times
ULN (for Arm B: <=1.5 times ULN), Serum Creatinine <=1.5 x ULN, Or Measured or
Calculated Creatinine Clearance >=45 mL/min, Left ventricular ejection fraction
>=lower limit of normal (LLN).
- For Arms A, B, C: Treatment with any FGFR inhibitor. For Arms B, C: Treatment with
any anti-cancer therapy (for biological anti-cancer therapies see criteria below.)
during the preceding 4 weeks or within 4 half-lives of the therapy, whichever is
longer (except: anti-cancer hormonal treatment of prostate cancer, breast cancer or
octreotide for treatment of carcinoid cancer).
- Receipt of any biological therapy within 6 weeks of the first dose of GSK3052230
- Unresolved toxicity of NCI CTCAE version 4.03 Grade 2 or higher from previous
anti-cancer therapy, except alopecia.
- Active malignancy other than the cancer under study. Subjects with a history of
completely resected non-melanomatous skin carcinoma or successfully treated in situ
carcinoma are eligible.
- Presence of uncontrolled infection
- Prior major surgery or trauma within 28 days before first dose of study drug
- Presence of any non-healing wound, fracture, or ulcer
- Any prohibited medication(s) as described in protocol
- Conditions likely to increase the potential for abdominal perforation or fistula
formation, including but not limited to:
Luminal intestinal cancers or bulky abdominal disease. Presence or history of abdominal
fistula, gastrointestinal perforation, peptic ulcer disease or intra-abdominal abscess
within the six months prior to the first dose of GSK3052230.
Other risk factors for perforation, such as acute diverticulitis, obstruction or previous
abdominal or pelvic radiation.
- Symptomatic leptomeningeal or brain metastases or spinal cord compression Note:
Subjects previously treated for these conditions that have had stable central nervous
system disease (verified with consecutive imaging studies) for >1 month, are
asymptomatic and off corticosteroids, or are on stable dose of corticosteroids for at
least 1 month prior to study Day 1 are permitted. Stability of brain metastases must
be confirmed with imaging. If subjects have been treated with gamma knife they can be
enrolled 2 weeks post-procedure as long as there are no post-procedure complications.
In addition, subjects treated or currently taking enzyme-inducing anticonvulsant are
allowed on study.
- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study drugs (GSK3052230, docetaxel, paclitaxel, carboplatin)
and or their excipients that contraindicate their participation.
- Known human immunodeficiency virus-positive serology, acquired immunodeficiency
syndrome (AIDS), or an AIDS-related illness.
- Prior organ or allogeneic stem cell transplant
- The following cardiac abnormalities:
Corrected QT (QTc) interval >=480 millisecond. History of acute coronary syndromes
(including unstable angina) within the past 24 weeks Coronary angioplasty or stenting
within the past 24 weeks. Class II, III, or IV heart failure as defined by the New York
Heart Association (NYHA) functional classification system.
Abnormal cardiac valve morphology (>= Grade 2) documented by echocardiogram (subjects with
Grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study).
History of known arrhythmias (except sinus arrhythmia and atrial fibrillation that is
controlled) within the past 24 weeks.
- Presence or history of hemoptysis (>1/2 teaspoon of red blood) 2 weeks prior to the
first dose of GSK3052230
- Any serious and/or unstable pre-existing medical, psychiatric disorder or other
conditions that could interfere with subject's safety, obtaining informed consent or
compliance to the study procedures.
- Current active liver or biliary disease (with the exception of Gilbert's syndrome or
asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease
per investigator's assessment).
- Pregnant, lactating or actively breast feeding females.
- French subjects: The French subject has participated in any study using an
investigational study treatment(s) during the previous 30 days.