| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10048683 |
| E.1.2 | Term | Advanced cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To evaluate the safety, tolerability, and dose-limiting toxicities (DLTs) and to determine the pharmacologically active dose (PAD) and maximum tolerated dose (MTD) of INCB054828, alone as a monotherapy and in combination with other therapies.
To assess the pharmacodynamics (PD) of INCB054828. |
|
| E.2.2 | Secondary objectives of the trial |
To assess preliminary efficacy by assessing the overall response rate
(ORR) of INCB054828 in subjects with measurable disease, alone as a
monotherapy and in combination with other therapies.
To evaluate the pharmacokinetics (PK) of INCB054828 and the effect of
food and other therapies on the PK of INCB054828. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects, age 18 years or older on day of signing consent.
2. Willingness to provide written informed consent for the study.
3. Part 1: Any advanced solid tumor malignancy.
Part 2: Subjects with measurable disease with documented FGF/FGFR alterations, including multiple myeloma and MPNs . For subjects enrolling in Part 2 with lead head and neck, vulvar, or anal cancer, must have evidence of positive HPV status. For BID dosing in Part 2, subjects must have a documented FGFR3 mutation or fusion-positive with advanced/metastatic bladder cancer.
Part 3:
1) Dose finding: subjects with solid tumor malignancies that have measurable disease for which treatment with gemcitabine + cisplatin, docetaxel, pembrolizumab, or trastuzumab is relevant.
2) Dose expansion: subjects with solid tumor malignancies that have measurable disease and are also harboring FGF/FGFR alterations for which treatment with gemcitabine + cisplatin, docetaxel, pembrolizumab, or trastuzumab is relevant.
4. Has progressed after prior therapy and either there is no further effective standard anticancer therapy available (including subject refuses or is intolerant) or the prescribed combination therapy for subjects enrolling in Part 3 is considered a relevant therapy for their diagnosis.
5. Life expectancy > 12 weeks.
6. ECOG performance status:
Part 1: 0 or 1.
Parts 2 and 3: 0, 1, or 2.
7. Archival tumor specimen (tumor block or 25 unstained slides, minimum number of slides is approximately15) or willingness to undergo a pretreatment tumor biopsy to provide a tumor block or 25 unstained slides (minimum number of slides is approximately 15). Archival tumor biopsies are acceptable at baseline and should be no more than 2 years old (preferably less than 1 year old and collected since the completion of the last treatment); subjects with samples older than 2 years old and/or with sequencing report from Foundation Medicine require approval from the sponsor medical monitor for exemption from the need for tumor biopsy or tumor sample requirement.
NOTE: For subjects in Part 1, fresh tumor biopsies for the purpose of determining study eligibility should be limited to tumors where tissue can be safely accessed. The medical monitor should be contacted before the subject is enrolled.
8. Women of childbearing potential (defined as women who have not undergone surgical sterilization with a hysterectomy and/or bilateral oophorectomy and are not postmenopausal or sterilized from chemo/radiotherapy, defined as ≥ 12 months of amenorrhea) must have a negative serum pregnancy test at screening and prior to the first dose on Cycle 1 Day 1. All women and men of childbearing potential must agree to take appropriate precautions to avoid pregnancy or fathering children (with at least 99%certainty) from screening through the safety follow-up visit (30-35 days after last dose). Subjects enrolled in Part 3 combination with INCMGA00012 should avoid pregnancy or fathering a child starting at screening through 6 months after the last dose of INCMGA00012. Permitted methods that are at least 99% effective in preventing pregnancy (Appendix A) should be communicated to the subject and their understanding confirmed. |
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| E.4 | Principal exclusion criteria |
•Treatment with other investigational study drug for any indication for any reason, or receipt of anticancer medications within 28 days before first dose of study drug (6 wks for mitomycin-C or nitrosoureas, 7 days for tyrosine kinase inhibitors), but may be eligible with approval from the sponsor's medical monitor (MM).
- Subjects must have recovered (≤ Grade 1 or pretherapy baseline) from AEs due to previously administered therapies.
•Prior receipt of a selective FGFR inhibitor within the last 6 months
•Laboratory parameters outside Protocol-defined range.
•Part 1 Dose Escalation:
- Hemoglobin < 10.0 g/dL (transfusions are permitted with approximately 2 weeks of washout required before enrolment (TFP)).
- Platelet count < 100 × 109/L
- Absolute neutrophil count < 1.5 × 109/L
- Total bilirubin > upper limit of normal (ULN) unless associated with subject's primary cancer and/or metastases and with MM approval (**Unless Associated)
- AST or ALT > ULN **Unless Associated
- ALP > ULN **Unless Associated
- Creatinine clearance ≤ 60 mL/min (< 30 mL/min for urothelial carcinoma) based on the site's standard formula
- Serum calcium outside of the institutional normal range (INR), or serum albumin-corrected calcium outside of INR if serum albumin is outside of INR
- Serum phosphorus outside of the ULN of INR
- Parathyroid hormone > 1.5 x ULN of INR
•Part 2 Expansion:
- Hemoglobin ≤ 9.0 g/dL (TFP)
- Platelet count ≤ 75 × 109/L
- Absolute neutrophil count ≤ 1.0 × 109/L
- Total bilirubin ≥ 1.5 × institutional ULN **Unless Associated
- AST or ALT ≥ 3 × ULN **Unless Associated
- ALP ≥ 2.5 × ULN **Unless Associated
- Creatinine clearance ≤ 40 mL/minute (< 30 mL/min for multiple myeloma or urothelial carcinoma) based on the site's standard formula
- Serum calcium outside of INR, or serum albumin-corrected calcium outside of INR if serum albumin is outside of INR
- Serum phosphorus outside of the ULN of INR
- Parathyroid hormone > 1.5 x ULN of INR
•Note: Hematological parameters do not apply to subjects with MPN.
•Part 3 Combination:
- Hemoglobin ≤ 9.0 g/dL (TFP)
- Platelet count ≤ 75 × 109/L
- Absolute neutrophil count ≤ 1.5 × 109/L
- Total bilirubin ≥ 1.5 × institutional ULN **Unless Associated
- AST or ALT ≥ 3 × ULN **Unless Associated
- ALP ≥ 2.5 × ULN **Unless Associated
- Creatinine clearance ≤ 40 mL/minute (< 30 mL/min for urothelial carcinoma) based on the site's standard formula
- International normalized ratio or prothrombin time > 1.5 × ULN, unless on warfarin
- Activated partial thromboplastin time > 1.5 × ULN
- Serum calcium outside of INR, or serum albumin-corrected calcium outside of INR when serum albumin is outside of INR
- Serum phosphorus outside of the ULN of INR
- Parathyroid hormone > 1.5 x ULN of INR
•History of a calcium/phosphate homeostasis disorder.
•History of hypersensitivity to any of the study drugs.
•History and/or current evidence of ectopic mineralization/calcification, except intratumoral calcification secondary to tumor necrosis or previous treatment (eg, transarterial chemoembolization, chemotherapy) and calcified lymph nodes and asymptomatic arterial or cartilage/tendon calcification.
•Current evidence of corneal disorder/keratopathy, including but not limited to bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjuctivitis, etc, confirmed by ophthalmologic examination.
•History or presence of an abnormal ECG that in the investigator's opinion is clinically meaningful. A screening QTc interval > 470 milliseconds, as corrected by Fridericia, is excluded. For subjects with an intraventricular conduction delay (QRS interval 120 msec), the JTc interval may be used in place of the QTc with sponsor approval. The JTcmust be ≤ 340 msec if JTc is used in place of the QTc.
•Prior radiotherapy within 2 weeks of study treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Evidence of fibrosis within a radiation field from prior radiotherapy is permitted with MM approval. A 1-wk washout period is permitted for palliative radiation to non–central nervous system disease with MM approval.
− Subjects enrolled into Part 3 (pembrolizumab or INCMGA00012 combination), should have a minimum of a 6-month washout period after thoracic radiotherapy if > 30 Gy was received.
•Part 3 (pembrolizumab group): Subjects who have received prior treatment with anti-PD1 therapy.
•Subjects receiving pembrolizumab or INCMGA00012 and have received a live vaccine within 28 days of planned start of study treatment. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Safety and tolerability will be assessed by monitoring frequency, duration, and severity of AEs; through physical examinations; by evaluating changes in vital signs and ECGs; and through clinical laboratory blood and urine sample evaluations.
• Pharmacodynamics of INCB054828 including serum phosphorus level. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Laboratory samples are taken per the study schedule of assessments. PK and PD samples are taken during the first cycle of treatment and the first cycle following any dose increase or decrease. |
|
| E.5.2 | Secondary end point(s) |
• Tumor response rates in those subjects with measurable disease as determined by the investigator assessment of response.
• Cmax, tmax, Cmin, AUC0-t, t½, and Cl/F. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Tumor assessment is to be performed at baseline and every 3 cycles of treatment until subject discontinues |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase I/ Phase II study combined |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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