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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, Afatinib (Gilotrif) and Pemigatinib (Pemazyre or INCB054828), to determine their safety and effectiveness for individuals with advanced solid tumors that cannot be surgically removed or have metastasized. Researchers aim to identify the highest doses that can be administered without severe side effects. This study may suit those with FGFR gene changes in their tumors who have already tried other unsuccessful treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that pemigatinib is approved for treating advanced cholangiocarcinoma, a type of liver cancer, indicating its reasonable safety for people with that condition. Studies suggest that pemigatinib can help control the disease in many patients, with usually manageable side effects.

Afatinib, another cancer treatment drug, is generally well-tolerated. Researchers are studying the safety of using afatinib with pemigatinib for certain advanced solid tumors. As this trial is in an early phase, researchers are determining the right doses that can be given safely without causing serious side effects.

In summary, both drugs have been used separately to treat cancers, and their combination is under careful study to ensure patient safety. Initial findings suggest that while side effects may occur, researchers are working to find a safe dosage. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Afatinib and Pemigatinib for solid tumors because these treatments offer a new approach for targeting FGFR-altered cancers, particularly cholangiocarcinoma. Unlike standard therapies, which often include chemotherapy or surgery, Afatinib and Pemigatinib work by specifically inhibiting FGFR pathways, potentially leading to more precise targeting of tumor cells. This targeted action not only aims to improve efficacy but also hopes to reduce side effects compared to conventional treatments. By addressing the molecular drivers of the cancer, these drugs could offer new hope for patients who have limited options with existing therapies.

What evidence suggests that this trial's treatments could be effective for advanced solid tumors?

Research has shown that Pemigatinib effectively treats tumors with FGFR2 changes, such as certain bile duct cancers, by stopping cancer cell growth. Studies have found that Pemigatinib works well in solid tumors with these changes and is already approved for advanced bile duct cancer. Afatinib, in contrast, blocks signals that help cancer cells grow. In this trial, participants will receive a combination of Afatinib and Pemigatinib. Early research suggests that combining Afatinib with Pemigatinib can overcome resistance by targeting different growth pathways. This combination might offer a new way to treat cancers that don't respond well to current treatments. ^{2 3 6 7 8}

Who Is on the Research Team?

Haley Ellis, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

Citations

1. withpower.com withpower.com/trial/phase-1-neoplasms-6-2024-8c8a3

Afatinib + 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 ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1040842824002075

Precision oncology targeting FGFRs: A systematic review ... Pemigatinib is a potent anti-FGFRs TKI now approved in advanced cholangiocarcinoma. Many clinical trials are ongoing to assess Pemigatinib efficacy in other ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12369749/

Targeted therapies and immunotherapies for unresectable ... Several phase I studies have previously demonstrated the efficacy and safety of pemigatinib in solid tumors, including CCA with FGF/FGFR alterations. The FIGHT- ...

4. cholangiocarcinoma.org cholangiocarcinoma.org/trials/a-phase-ia-ib-study-of-the-combination-of-the-fgfr-inhibitor-pemigatinib-and-the-egfr-inhibitor-afatinib-in-advanced-refractory-solid-tumors/

A Phase Ia/Ib Study of the Combination of the FGFR ... Preclinical work demonstrates this combination is effective in overcoming treatment resistance by blocking bypass growth pathways. Patients with and without ...

5. tandfonline.com tandfonline.com/doi/full/10.2217/fon-2020-0429

FIGHT-302: first-line pemigatinib vs gemcitabine plus ... Data from a Phase I/II dose-finding study (FIGHT-101; NCT02393248) demonstrated preliminary efficacy and manageable toxicities after treatment with pemigatinib ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06302621

Pemigatinib + Afatinib in Advanced Refractory Solid Tumors This study is researching whether the combination of Afatinib and Pemigatinib is safe and effective in FGFR altered unresectable or metastatic advanced ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12078806/

Safety and efficacy of pemigatinib in patients with ... This systematic review suggests that pemigatinib has modest therapeutic efficacy in CCA patients, with a considerable proportion achieving disease control.

8. ajp.amjpathol.org ajp.amjpathol.org/article/S0002-9440(24)00446-2/fulltext

Cholangiocarcinoma Targeted Therapies This review examines the clinical efficacy and mechanisms of resistance associated with these treatments, as well as insights into the molecular and biological ...