hepatocellular carcinoma or other solid tumors

The purpose of this study is to determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of FGF401 in patients with hepatocellular carcinoma or other solid tumors characterized by positive FGFR4 and KLB expression; and to estimate the preliminary anti-tumor activity of FGF401 in these populations. Based on preclinical studies, FGF401 is a highly potent, selective FGFR4 inhibitor, thereby making it a good candidate for use in the clinic. Positive prediction for sensitivity to FGF401 was identified to be associated with positive expression of FGFR4, KLB and FGF19.

FGF401

FGF401

hard gelatin capsule

10, 50, 100

Efficacy assessments
Tumor assessment per RECIST v1.1

Safety assessments
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital signs and ECGs

Other assessments
Plasma PK parameters
Pharmacodynamic assessment on pre- and post- treatment blood samples and newly obtained tumor samples

Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures
2. Patients (male or female) ≥ 18 years of age
3. ECOG Performance Status ≤ 1
4. Presence of at least one measurable lesion according to RECIST v1.1 (see Section 14.1). For HCC patients, lesions previously treated with loco-regional therapy, such as radiation therapy, hepatic arterial embolization, radiofrequency ablation, and percutaneous interventional therapy should not be considered measurable unless progression is noted at baseline.
5. Patients must be suitable and willing to undergo a mandatory tumor biopsy
procedure at molecular pre-screening if no existing tumor sample collected after the latest anti-neoplastic treatment failure (phase I and II) and on treatment (mandatory in phase I and optional in phase II) according to treating institution’s guidelines and requirements for such procedure.
6. Patients with confirmed positive expression of FGFR4 and KLB at molecular pre- screening. In the phase II part, at least 20 patients each in Groups 1 and 2 with confirmed positive expression of FGFR4 and KLB and FGF19 at molecular pre-screening. The biomarker positivity will be defined by a Novartis designated laboratory. Patients with FGFR4 mutations can be enrolled in the study following discussion and agreement with Novartis.
7. Phase I part:
a. Patients with HCC or advanced solid tumors, who have progressed despite standard therapies, are intolerant of standard therapy, or for whom no standard therapy exists.
b. For HCC patients:
a) Diagnosis of advanced HCC according to the AASLD Guidelines
b) HCC stage C according to the BCLC staging classification
c) Current cirrhotic status of Child-Pugh class A (5-6 points), with no encephalopathy and/or ascites. Child-Pugh status must be calculated based on clinical findings and laboratory results during the Screening period.
8. Phase II part:
a. Group 1: HCC patients from Asian countries
b. Group 2: HCC patients from non-Asian regions
For Group 1 and 2:
a) Diagnosis of advanced HCC according to the AASLD Guidelines
b) HCC stage C according to the BCLC staging classification
c) Prior systemic treatment with sorafenib for advanced HCC with documented disease progression during or after discontinuation of sorafenib treatment, or intolerance to sorafenib treatment. Specifically, this can be defined as:
• Documented radiological confirmation (radiology scans or report) of disease progression during or after sorafenib treatment. [For France only: patients must have received at least 8 weeks of prior sorafenib treatment.]
• Intolerance to sorafenib (at any dose and/or duration) is defined as documented sorafenib-related Grade 3 or 4 adverse events that led to sorafenib discontinuation.
d) Current cirrhotic status of Child-Pugh class A (5-6 points), with no encephalopathy and/or ascites. Child-Pugh status must be calculated based on clinical findings and laboratory results during the Screening period.
c. Group 3: Patients with other advanced solid tumor
a) Patients have progressed despite standard therapies, are intolerant of standard therapy, or for whom no standard therapy exists.

Patients eligible for this study must not meet any of the following criteria:
1. Previous treatment with a selective FGF19-FGFR4 targeted therapy and/or pan-FGFR inhibitor.
2. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral FGF401 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, small bowel resection).
3. Patient have received prior therapies within the following time frames prior to the first dose of study treatment:
a. For HCC patients in Phase II only: previous systemic anti-cancer therapy other than sorafenib
b. For HCC patients in Phase II only: any other anti-cancer therapy
(including locoregional therapy) after disease progression during or after sorafenib treatment
c. For other solid tumor patients: The last dose of conventional cytotoxic chemotherapy: ≤2 weeks (≤6 weeks for nitrosoureas and mitomycin-C)
d. For other solid tumor patients: Biological therapy (e.g., antibodies): ≤4 weeks
e. Non-cytotoxic small molecule therapeutics (e.g., sorafenib): ≤5 half-lives or ≤2 weeks (whichever is longer)
f. Previous wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) ≤ 4 weeks and limited field radiation for palliation ≤ 2 weeks
g. Major surgery: ≤2 weeks
h. Participation in a prior investigational study within 7 days or within 5 half-lives of the investigational product, whichever is longer
Note: exceptions to the above prior therapy timeframes are possible, on a case by case basis, following discussion and mutual agreement between Investigator and Novartis.
4. Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 3 years prior to study entry; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
5. Symptomatic CNS metastases which are neurologically unstable or requiring increasing doses of steroids to control their CNS disease.
Note: Patients with controlled CNS metastases may participate in this trial. The patient must have completed radiotherapy or surgery for CNS metastases >2 weeks prior to study entry. Patients must be neurologically stable, having no new neurologic deficits on clinical examination, and no new findings on CNS imaging. If patients require steroids for management of CNS metastases, they must have been on a stable dose of steroids for two weeks preceding study entry.
6. Any medical condition that would, in the investigator’s judgment, prevent the patient’s participation in the clinical study due to safety concerns or compliance with clinical study procedures. Any severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.
7. Ongoing active diarrhea requiring medications (e.g. bile acid sequestrant (BAS), loperamide)
8. Irritable bowel syndrome with signs/symptoms or requires medications
9. Current evidence of calcium-phosphate homeostasis, defined as:
a. Inorganic phosphorus > 5.5 mg/dL
b. Total calcium > 11.5 mg/dL
c. Ionized serum calcium > 1.5 mmol/L
d. Patients with current evidence of endocrine alteration of calcium/phosphate homeostasis, e.g. parathyroid disorders, tumor lysis, tumoral calcinosis etc.
10. Patient having out of range laboratory values defined as:
Hematology
a) Hemoglobin ≤ 9 g/dL (SI Units: 90 g/L)
b) Platelet count < 75000/mm3
c) Absolute neutrophil count (ANC) < 1500/mm3
Chemistry
a) Total bilirubin ≥ 2 mg/dL
b) AST and/or ALT > 3 x ULN
c) Serum creatinine > 1.5 x ULN and/or creatinine clearance ≤ 45 mL/min
Coagulation: PT ≥ 4 seconds or INR ≥ 1.7
11. Patients receiving treatment with CYP1A2, CYP2C9 and CYP3A4/5 substrates with a narrow therapeutic index (NTI) that cannot be discontinued for the duration of the study (refer to Appendix 4).
12. Patients receiving treatment with long acting proton pump inhibitors that cannot be discontinued 3 days prior to the start of study treatment and during the course of the study (refer to Appendix 4).
13. Patients receiving strong BSEP efflux transporter inhibitors that cannot be discontinued 3 days prior to the start of study treatment and during the course of the study (refer to Appendix 4).
14. Pregnant or nursing (lactating) women.
15. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing of study treatment and for 3 days after discontinuation of treatment. Highly effective contraception methods include:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• Male sterilization (at least 6 months prior to screening). For female subjects on the study the vasectomized male partner should be the sole partner for that subject.
• Combination of any two of the following (a+b or a+c, or b+c):
a. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
In case of use of oral contraception women should have been stable on the same pill for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
16. Sexually active males unless they use a condom during intercourse while taking drug and for 3 days after the last dose of study drug, and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid.