E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Male and female participants at least 18 years of age who have a solid tumor malignancy with an activating FGFR mutation or translocation who have progressed on prior therapies and have no available standard treatment options |
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E.1.1.1 | Medical condition in easily understood language |
Participants who have a solid tumor malignancy |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065147 |
E.1.2 | Term | Malignant solid tumor |
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 efficacy of pemigatinib in participants with locally advanced/metastatic or surgically unresectable solid tumor malignancy with an activating FGFR mutation or translocation. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate other clinical efficacy measurements of pemigatinib in participants with locally advanced/metastatic or surgically unresectable solid tumor malignancy with an activating FGFR mutation and/or translocation. • Safety and tolerability of pemigatinib. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age 18 years or older, inclusive at the time of signing the informed consent. 2. Histologically or cytologically confirmed solid tumor malignancy that is advanced or metastatic (Stage IIIB or IV per the AJCC Cancer Staging Manual, 8th ed; AJCC 2018) or is surgically unresectable. 3. Radiographically measurable disease (per RECIST v1.1 or RANO for primary brain tumors). Tumor lesions located in a previously irradiated area, or in an area subjected to other loco-regional therapy, are considered measureable if progression has been clearly demonstrated in the lesion. 4. Documentation of an FGFR1-3 gene mutation or translocation (Section 8.5.1 and Appendix C of the protocol). Participants will be assigned to 1 of 3 cohorts: • Cohort A: FGFR1-3 in-frame fusions or FGFR2 rearrangements* (n = 60) • Cohort B: Known or likely activating mutations (excluding kinase domain) in FGFR1-3 included in Appendix C of the protocol (n = 90) • Cohort C: Known activating mutations in the kinase domain of FGFR1-3, other likely activating FGFR1-3 mutations or FGFR1/FGFR3 rearrangements* (requires consultation with the sponsor) (n = 20)*Only FGFR fusions or rearrangements with an intact kinase domain are eligible. 5. Must have objective progression after at least 1 prior therapy, and must have no therapy available that is likely to provide clinical benefit. Participants who are intolerant to or decline the approved therapy are eligible only if they have no therapy available that is likely to provide clinical benefit. 6. ECOG performance status 0 to 2. 7. Baseline archival tumor specimen (if less than 12 months from date of screening) or willingness to undergo a pretreatment tumor biopsy to obtain the specimen. Must be a tumor block or approximately 15 unstained slides from biopsy or resection of primary tumor or metastasis. 8. Willingness to avoid pregnancy or fathering children based on the criteria below. a. Men must agree to take appropriate precautions to avoid fathering children (with at least 99% certainty) from screening through 90 days after the last dose of study drug(s)/treatment and must refrain from donating sperm during this period. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A of the protocol) should be communicated to the participants and their understanding confirmed. b. Women of childbearing potential must have a negative serum pregnancy test at screening and before the first dose on Day 1 and must agree to take appropriate precautions to avoid pregnancy (with at least 99% certainty) from screening through safety follow-up. Permitted methods that are at least 99% effective in preventing pregnancy (see Appendix A of the protocol) should be communicated to the participants and their understanding confirmed. c. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or bilateral oophorectomy OR ≥ 12 months of amenorrhea) are eligible. |
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E.4 | Principal exclusion criteria |
1. Prior receipt of a selective FGFR inhibitor. 2. Receipt of anticancer medications or investigational drugs for any indication or reason within 28 days before first dose of pemigatinib. Participants must have recovered (≤ Grade 1, as per CTCAE v5.0, or at pretreatment baseline) from AEs from previously administered therapies (excluding alopecia). 3. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor embolization). 4. Candidate for potentially curative surgery. 5. Current evidence of clinically significant corneal (including, but not limited to, bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivitis) or retinal disorder (including, but not limited to, macular/retinal degeneration, diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic examination. 6. Radiation therapy administered within 2 weeks of enrollment/first dose of study treatment. Participants 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 medical monitor approval. A 1-week washout is permitted for palliative radiation to non-CNS disease. 7. Untreated brain or CNS metastases or brain or CNS metastases that have progressed (eg, evidence of new or enlarging brain metastasis or new neurological symptoms attributable to brain or CNS metastases). Participants who have previously treated and clinically stable brain or CNS metastases are eligible if there is no evidence of progression for at least 4 weeks after CNS-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT scan) during the screening period, and if they are on a stable or decreasing dose of corticosteroids for at least 1 week. Note: Participants with progressing primary brain tumors are allowed if they have no new neurological symptoms and are on a stable or decreasing dose of corticosteroids for at least 1 week. 8. Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
ORR in Cohort A, defined as the proportion of participants in Cohort A who achieve a CR or PR based on RECIST v1.1 or RANO. ORR in Cohort B, defined as the proportion of participants in Cohort B who achieve a CR or PR based on RECIST v1.1 or RANO. An independent radiological review committee will determine response. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The schedule for assessments will be performed according to the schedule of activities reported in the protocol. The schedule for efficacy assessments will be at screening (this will be considered the baseline scan), every 9 weeks (every 3 cycles), and then at EOT (if applicable). Imaging should continue in 9-week intervals regardless of delays in cycle starts. |
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E.5.2 | Secondary end point(s) |
• PFS, defined as the time from first dose until progressive disease (according to RECIST v1.1 or RANO and assessed by an ICR) or death (whichever is first) in Cohorts A and B, respectively. • DOR, defined as the time from the date of first assessment of CR or PR until the date of the first progressive disease by an ICR per RECIST v1.1 or RANO, or death (whichever is first) in Cohorts A and B, respectively. • OS, defined as the time from first dose of study drug to death of any cause in Cohorts A and B, respectively. • Safety and tolerability, as assessed by the occurrence of TEAEs and treatment-related AEs according to NCI CTCAE v5.0, physical exam changes, vital sign changes, laboratory evaluations, and ECGs in each cohort. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The schedule for assessments will be performed according to the schedule of activities reported in the protocol. The schedule for efficacy assessments will be at screening (this will be considered the baseline scan), every 9 weeks (every 3 cycles), and then at EOT (if applicable). Imaging should continue in 9-week intervals regardless of delays in cycle starts. Adverse events will be monitored from the time the participant signs the ICF until at least 30 to 35 days after the last dose of study drug or until the start of new anticancer therapy, whichever occurs first. |
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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 | No |
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) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
Denmark |
France |
Germany |
Israel |
Italy |
Japan |
Korea, Republic of |
Spain |
Switzerland |
United Kingdom |
United States |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |