Afatinib + Pemigatinib for Solid Tumors

Overseen By Haley Ellis, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Massachusetts General Hospital

Must not be taking: Strong p-gp inhibitors, Potent CYP3A4 inducers

Disqualifiers: HIV, Active CNS metastases, Uncontrolled infection, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 19

70 Participants Needed

Trial Summary

What is the purpose of this trial?

This study is researching whether the combination of Afatinib and Pemigatinib is safe and effective in FGFR altered unresectable or metastatic advanced solid tumors. The study is also trying to discover the highest doses of the study drugs that can be administered without causing any intolerable side effects. This research study involves the study drugs Afatinib and Pemigatinib.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take certain medications like strong p-gp inhibitors or potent CYP3A4 inhibitors or inducers within 14 days before starting the study treatment. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug combination Afatinib and Pemigatinib for solid tumors?

Pemigatinib has shown effectiveness in treating tumors with FGFR2 alterations, such as cholangiocarcinomas, by inhibiting the growth of cancer cells. Afatinib has demonstrated antitumor activity when combined with other drugs in patients with advanced solid tumors, suggesting potential benefits when used with Pemigatinib. ^{1 2 3 4 5}

Is the combination of Afatinib and Pemigatinib safe for humans?

Pemigatinib has shown an acceptable safety profile in patients with advanced solid tumors, with some experiencing serious side effects. Afatinib, used for lung cancer, generally has manageable side effects like diarrhea and skin rash, which can be controlled by adjusting the dose. ^{1 3 5 6 7}

What makes the drug combination of Afatinib and Pemigatinib unique for treating solid tumors?

The combination of Afatinib and Pemigatinib is unique because it targets two different pathways involved in cancer growth: Afatinib inhibits the ErbB family of proteins, which are involved in cell growth and division, while Pemigatinib selectively inhibits fibroblast growth factor receptors (FGFR) 1-3, which are often altered in certain tumors. This dual approach may offer a more comprehensive treatment for solid tumors with specific genetic alterations. ^{1 2 5 6 7}

Research Team

Haley Ellis, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

This trial is for individuals with advanced solid tumors that can't be removed by surgery or have spread (metastatic), and whose tumors have specific genetic alterations called FGFR. The exact eligibility criteria are not provided, but typically participants must meet certain health standards to ensure safety.

Inclusion Criteria

Patients able to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation

Patients with measurable or non-measurable disease as determined by RECIST 1.1

My organs are functioning well.

Exclusion Criteria

Patients living outside the US

Lactating or breastfeeding individuals during the study or within 30 days of the last dose of study intervention

I am allergic to afatinib, pemigatinib, or their ingredients.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Phase 1a dose escalation to determine the maximum tolerated dose of Pemigatinib and Afatinib in patients with FGFR-altered refractory advanced solid tumors

3 weeks

Cycle 1 Day 1 to Cycle 1 Day 21

Dose Expansion

Phase 1b dose expansion to evaluate safety and efficacy in FGFR inhibitor-naïve and FGFR-inhibitor-pretreated cholangiocarcinoma cohorts

6 months

Every 9 weeks during treatment

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 1 year

Every 9 weeks during treatment and off study

Treatment Details

Interventions

• Afatinib
• Pemigatinib

Trial Overview The study is testing the combination of two drugs, Afatinib and Pemigatinib, to see if they're safe and effective against advanced solid tumors with FGFR alterations. It also aims to find the highest doses patients can take without severe side effects.

Participant Groups

Group I: DOSE ESCALATION PHASE 1A PEMIGATINIB + AFATINIB Experimental Treatment 2 Interventions

In the phase 1a dose escalation study participants with FGFR-altered refractory advanced solid tumors will be enrolled. This research study involves the study drugs Afatinib and Pemigatinib.

Group II: COHORT 2: EXPANSION PHASE 1B COHORT 2 MTD/RP2D PEMIGATINIB + AFATINIB FGFR INHIBITOR-PRETREATED Experimental Treatment 2 Interventions

In the phase Ib dose expansion study, patients with FGFR-altered cholangiocarcinoma will be recruited into 2 cohorts: FGFR inhibitor-naïve cholangiocarcinoma and FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. Cohort 2 will enroll patients with FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. This research study involves the study drugs Afatinib and Pemigatinib.

Group III: COHORT 1: EXPANSION PHASE 1B COHORT 1 MTD/RP2D PEMIGATINIB + AFATINIB FGFR INHIBITOR-NAIVE Experimental Treatment 2 Interventions

In the phase Ib dose expansion study, patients with FGFR-altered cholangiocarcinoma will be recruited into 2 cohorts: FGFR inhibitor-naïve cholangiocarcinoma and FGFR-inhibitor-pretreated and resistant cholangiocarcinoma. Cohort 1 will enroll patients with FGFR inhibitor-naïve cholangiocarcinoma. This research study involves the study drugs Afatinib and Pemigatinib.

Afatinib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Gilotrif for:

• Non-small cell lung cancer

Approved in European Union as Giotrif for:

• Non-small cell lung cancer

Approved in Canada as Gilotrif for:

• Non-small cell lung cancer

Approved in Japan as Giotrif for:

• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Boehringer Ingelheim

Industry Sponsor

Trials

2,566

Recruited

16,150,000+

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

Findings from Research

Pemigatinib is an effective treatment for patients with advanced cholangiocarcinoma that have FGFR2 genomic alterations, showing a 35.5% objective response rate after a median follow-up of 17.8 months in a phase II study.

The drug has a manageable safety profile, with common side effects including changes in blood phosphate levels, fatigue, and gastrointestinal issues, leading to its accelerated approval by the FDA for specific cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A drug safety evaluation of pemigatinib for advanced cholangiocarcinoma. Uson, PLS., Bearss, J., Babiker, HM., et al.[2023]

INCB054828 (pemigatinib) is a selective inhibitor of FGFR1, 2, and 3, showing potent inhibition in preclinical studies with IC50 values of 0.4, 0.5, and 1.0 nM, respectively, indicating its potential effectiveness against tumors with FGFR alterations.

The drug demonstrated significant antitumor effects in xenograft models with FGFR mutations and showed improved outcomes when combined with cisplatin, suggesting a promising therapeutic strategy for cancer patients with specific FGFR genetic changes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models. Liu, PCC., Koblish, H., Wu, L., et al.[2020]

In a phase I study involving 53 patients with advanced solid tumors, the combination of afatinib and pemetrexed showed a manageable safety profile, with diarrhea and fatigue being the most common side effects.

The maximum tolerated dose (MTD) was determined to be 30 mg for continuous dosing and 50 mg for pulsed dosing of afatinib, with both dosing schedules demonstrating disease control in a significant number of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors. Chu, QS., Sangha, R., Hotte, SJ., et al.[2021]

Pemigatinib has shown effectiveness in treating patients with cholangiocarcinomas that have FGFR2 fusions or rearrangements, indicating its potential as a targeted therapy for this specific cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemigatinib Is Active in Some FGFR2-Altered Cholangiocarcinomas. [2021]

In the phase I/II FIGHT-101 study involving 128 patients with advanced malignancies, pemigatinib demonstrated a manageable safety profile with no dose-limiting toxicities and a recommended phase II dose of 13.5 mg once daily.

The treatment showed preliminary efficacy, particularly in patients with FGFR fusions/rearrangements, achieving a 25% response rate, and prompting further studies in cholangiocarcinoma and other tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. Subbiah, V., Iannotti, NO., Gutierrez, M., et al.[2022]

In a phase I trial involving 12 Chinese patients with advanced solid tumors, pemigatinib showed acceptable safety and tolerability, with 25% of patients experiencing grade 3 or higher adverse events.

The drug demonstrated preliminary efficacy, with partial responses observed in two patients with specific FGFR mutations, indicating its potential as a targeted therapy for tumors with FGF/FGFR alterations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and efficacy of pemigatinib (a selective inhibitor of fibroblast growth factor receptor 1-3) monotherapy in Chinese patients with advanced solid tumors: a phase i clinical trial. Deng, T., Zhang, L., Shi, Y., et al.[2023]

Afatinib is an effective oral treatment for adults with advanced non-small cell lung cancer (NSCLC) who have specific activating EGFR mutations, showing significantly prolonged progression-free survival compared to standard chemotherapy regimens in two phase III trials.

The drug has a manageable safety profile, with common side effects like diarrhea and rash being effectively controlled through dose adjustments, making it a valuable option for treatment-naïve patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Afatinib: a review of its use in the treatment of advanced non-small cell lung cancer. Keating, GM.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

A drug safety evaluation of pemigatinib for advanced cholangiocarcinoma. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Pemigatinib Is Active in Some FGFR2-Altered Cholangiocarcinomas. [2021]

5. England pubmed.ncbi.nlm.nih.gov

FIGHT-101, a first-in-human study of potent and selective FGFR 1-3 inhibitor pemigatinib in pan-cancer patients with FGF/FGFR alterations and advanced malignancies. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, pharmacodynamics and efficacy of pemigatinib (a selective inhibitor of fibroblast growth factor receptor 1-3) monotherapy in Chinese patients with advanced solid tumors: a phase i clinical trial. [2023]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Afatinib: a review of its use in the treatment of advanced non-small cell lung cancer. [2022]