A Phase 2 study of zanidatamab in patients with HER2-expressing tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Jazz Pharmaceuticals Ireland Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Mar 2026 → ongoing

Decision date (initial)

2025-11-13

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Jazz Pharmaceuticals Ireland Limited.

External identifiers

EU CT number

2024-516551-41-00

ClinicalTrials.gov

NCT06695845

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Efficacy, Pharmacokinetic, Therapy, Safety

To evaluate the antitumor activity of zanidatamab monotherapy in participants with locally advanced, unresectable, or metastatic HER2-overexpressing (IHC 3+) solid tumors"

Secondary objectives 5

1. 1. To assess other antitumor efficacy parameters of zanidatamab monotherapy in participants with locally advanced, unresectable, or metastatic HER2-overexpressing (IHC 3+) solid tumors
2. 2. To evaluate the safety and tolerability of zanidatamab monotherapy in participants with locally advanced, unresectable, or metastatic HER2-overexpressing (IHC 3+) solid tumors
3. 3. To evaluate the PK of zanidatamab
4. 4. To evaluate the immunogenicity of zanidatamab
5. 5. To evaluate participant-reported tolerability of zanidatamab monotherapy in participants with locally advanced, unresectable, or metastatic HER2-overexpressing (IHC 3+) solid tumors

Conditions and MedDRA coding

Patients with HER2-expressing solid tumors

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

IPD plan description

investigational medicine not yet approved by EMA or FDA for this indication

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Is at least 18 years of age inclusive at the time of signing the informed consent (or the legal age of adulthood per country-specific regulations).
2. 2. Participants with locally advanced, unresectable, or metastatic solid tumors (except BTC, defined as gallbladder cancer or cholangiocarcinoma) who have progressed following at least 1 prior systemic treatment for metastatic or advanced disease and have no available treatment options that have confirmed benefit. Prior treatment with HER2-targeted therapy is not permitted (Cohort 1 only). For participants with breast cancer (Cohort 2) or GEA (Cohort 3), prior HER2-targeted therapy is permitted and prior therapy with T-DXd is required.
3. 3. HER2 status: HER2 overexpression (IHC 3+) must be determined by a sponsordesignated central laboratory. For HER2 testing of breast cancer, the breast cancer algorithm scoring per current ASCO/CAP guidelines must be used. For HER2 testing of tumors other than breast cancer, the gastric algorithm scoring per current ASCO/CAP guidelines must be used. • All participants must have adequate tumor sample for submission for central HER2 testing. Submission of FFPE tumor tissue block is strongly preferred. If a tumor tissue block is not available, discussion with the sponsor should occur. • Archival FFPE tumor tissue blocks must be < 2 years from the date of biopsy or resection to the start of prescreening or screening. The most recently available archival or new FFPE tissue specimen should be used to determine HER2 status eligibility. If available, the tissue that is submitted for Cohort 2 and 3 participants who have received prior T-DXd should be obtained after T-DXd treatment. • Specimens with limited tumor content, FNA, or bone decalcified samples will not be accepted for HER2 testing. Additional details on sample requirement will be provided in the laboratory manual.
4. 4. This inclusion criterion was merged with inclusion criterion #3 in Protocol Amendment 02. To maintain the original protocol numbering list, this criterion was intentionally left blank.
5. 5. Presence of at least 1 measurable lesion as assessed by ICR at screening based on RECIST version 1.1.
6. 6. Has Eastern Cooperative Oncology Group performance status of 0 or 1.
7. 7. Has a life expectancy of at least 3 months, in the opinion of the investigator.
8. 8. Participants with history of treated and stable CNS metastases are eligible, provided the following criteria are met: a. Participants must also have measurable metastatic disease with HER2 overexpression (IHC 3+) outside the CNS. b. Participants with treated CNS metastases that are no longer symptomatic may be included in the study if they recovered to ≤ Grade 1 (CTCAE version 5.0 or higher) or baseline from the acute toxic effect associated with the treatment ≥ 7 days prior to Cycle 1 Day 1. See Exclusion Criterion #3 for requirements of recovery from prior toxicity. (Note: Participants still receiving corticosteroids for brain metastasis must be on stable or decreasing doses within 14 days of Cycle 1 Day 1, and participants must have no requirement for anticonvulsants within 14 days of Cycle 1 Day 1. Anticonvulsants are permitted for pre-existing well-controlled seizure disorder.) c. Prior stereotactic radiosurgery or stereotactic radiotherapy should be completed at least 7 days (≥ 7 days) before the first dose of study intervention. A minimum of 14 days must have elapsed between the end of whole brain radio therapy and the first dose of study intervention.
9. 9. Has adequate hematologic parameters defined as follows: a. Absolute neutrophil count of at least 1000/mm3 (≥ 1000/mm3). b. Platelet count of at least 75,000 (≥ 75,000); participants must not have had platelet transfusion within 30 days of the Screening Visit laboratory draw. c. Hemoglobin of at least 8 g/dL (≥ 8 g/dL); participants with chronic anemia (other than autoimmune hemolytic anemia) that is supported by intermittent red blood cell transfusions are eligible.
10. 10. Has adequate hepatic function defined as follows: a. Total serum bilirubin of no more than 1.5 × ULN (≤ 1.5 × ULN) or less than 3 × ULN (< 3 × ULN) in the presence of Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastasis at baseline. b. Aspartate aminotransferase no more than 3.0 × ULN (≤ 3.0 × ULN) per institutional values (no more than 5.0 × ULN [≤ 5.0 × ULN] if liver metastases are present). c. Alanine aminotransferase no more than 3.0 × ULN (≤ 3.0 × ULN) per institutional values (no more than 5.0 × ULN [≤ 5.0 × ULN] if liver metastases are present).
11. 11. Has creatinine clearance of at least 30 mL/minute (ie, ≥ 30 mL/minute) as calculated per local institutional guidelines.
12. 12. Has LVEF of at least 50% (ie, ≥ 50%) as determined by either echocardiogram or multiple gated acquisition scan obtained within 4 weeks before the first dose of study intervention.
13. 13. Participant agrees to the following based on sex assigned at birth. a. Male participants: Male participants are eligible to participate if they agree to the following during the intervention period and for at least 4 months after the last dose of study intervention: • Refrain from donating fresh unwashed semen. • Use contraception as follows: − Use a male condom and should also be advised of the benefit of a female partner using a highly effective method of contraception, as a condom may break or leak, when having sexual intercourse with a WOCBP who is not currently pregnant. − Agree to use male condom when engaging in any activity that allows for passage of ejaculate to another person. b. Female participants: • A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies: − Is a WONCBP as defined in Appendix 4 Contraceptive and Barrier Guidance. OR − Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, as described in Appendix 4 Contraceptive and Barrier Guidance, during the study intervention period and for at least 4 months after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study intervention. • A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 3 days before the first dose of study intervention (Section 8.3.6 Pregnancy Testing). − If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. • Additional requirements for pregnancy testing during and after study intervention are provided in Section 8.3.6 Pregnancy Testing. • The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
14. 14. Is capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

Exclusion criteria 18

1. 1. Has known or suspected leptomeningeal disease and/or untreated brain metastasis.
2. 2. Has uncontrolled or significant cardiovascular disease, including any of the following: a. History of myocardial infarction within 6 months before Cycle 1 Day 1. b. Troponin levels consistent with myocardial infarction as defined by the manufacturer’s specifications within 28 days prior to Cycle 1 Day 1. c. History of symptomatic congestive heart failure (New York Heart Association Class II to IV). d. To maintain the original protocol numbering list, this criterion was intentionally left blank. e. Ventricular arrhythmia requiring therapy.
3. 3. Has ongoing toxicity related to prior cancer therapy that has not recovered to Grade 1 (ie, ≤ Grade 1, CTCAE version 5.0 or higher) severity at the time of Cycle 1 Day 1, with the following exceptions: a. Alopecia. b. Neuropathy resolved or recovered and no higher than Grade 2 (ie, ≤ Grade 2) in severity at the time eligibility is assessed. c. Congestive heart failure that was no more than Grade 1 (ie, ≤ Grade 1) in severity at the time of occurrence and resolved completely.
4. 4. Has uncontrolled infection or requiring IV antibiotics, antivirals, or antifungals within 14 days of Cycle 1 Day 1.
5. 5. Has known HIV infection. Participants should be tested for HIV during the Screening Visit if required by local regulations or institutional review board/independent ethics committee.
6. 6. Has active hepatitis B or C infection. a. Participants who are hepatitis B surface antigen positive are eligible if they have hepatitis B virus deoxyribonucleic acid less than 500 IU/mL (<500 IU/mL). b. Participants positive for hepatitis C antibody are eligible only if polymerase chain reaction is negative for hepatitis C ribonucleic acid.
7. 7. Has an active SARS-CoV-2 infection. Participants with prior infection that has resolved per investigator opinion/local institutions’ requirements and screening guidance are eligible.
8. 8. Has a history of life-threatening hypersensitivity to mAbs or to recombinant proteins or excipients in the drug formulation of zanidatamab.
9. 9. Has any serious underlying medical or psychiatric condition that would impair the ability of the participant to receive or tolerate the planned treatment at the investigational site.
10. 10. Has any issue or condition that, in the opinion of the investigator, would contraindicate the participant’s participation in the study or confound the results of the study.
11. 11. Prior treatment with HER2-targeted therapy (Cohort 1 only).
12. 12. Has a history of trauma or major surgery within 4 weeks prior to Cycle 1 Day 1.
13. 13. Was treated with systemic antineoplastic therapy, including hormonal therapies for breast cancer, or any investigational therapy within 4 weeks or 5 half-lives (whichever is longer) prior to Cycle 1 Day 1. An exception to this is antibody-based anticancer therapy, which requires a ≥ 4 weeks washout period. A washout period of 14 days prior to Cycle 1 Day 1 is required after the last dose of radiation therapy. 14. Received zanidatamab at any time prior to the current
14. 14. Received zanidatamab at any time prior to the current study.
15. 15. CRC participants with known KRAS/NRAS and BRAF mutations.
16. 16. NSCLC participants with known ALK, EGFR mutations and ROS1 fusion.
17. 17. Female participants who are breastfeeding or pregnant, and female and male participants planning a pregnancy.
18. 18. Prior or concurrent invasive malignancy other than the disease under study, whose natural history or treatment has, in the opinion of the investigator or medical monitor, the potential to interfere with the safety or efficacy assessment of the investigational regimen.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. cORR per ICR as assessed by RECIST version 1.1

Secondary endpoints 5

1. 1. DOR per ICR as assessed by RECIST version 1.1 • Investigator-assessed cORR and DOR per RECIST version 1.1 • ICR- and investigator-assessed (per RECIST version 1.1): − TTR − DCR − PFS • OS
2. 2. Frequency of TEAEs and SAEs as graded by • NCI CTCAE version 5.0 or higher • Frequency of dose reductions • Frequency of discontinuations of treatment due to TEAEs
3. 3. Serum concentrations of zanidatamab
4. 4. Frequency, duration, and time of onset of anti-zanidatamab antibodies and neutralizing antibodies, if applicable
5. 5. The frequency and severity of symptomatic AEs prior to first dose of study intervention and during the on-treatment period, based on the PRO-CTCAE and EORTC Item Library • The percent of all treated participants reporting each level of side-effect bother while on treatment, based on the FACIT-GP5 •The level of side-effect bother reported over time per participant, summarized as the percent of time on treatment with high side-effect bother, based on the FACIT-GP5

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Jazz Pharmaceuticals Ireland Limited

Sponsor organisation

Jazz Pharmaceuticals Ireland Limited

Address

5th Floor, Waterloo Exchange, Waterloo Road Waterloo Exchange Waterloo Road

City

Dublin 4

Postcode

D04 E5W7

Country

Ireland

Scientific contact point

Organisation

Jazz Pharmaceuticals Ireland Limited

Contact name

Medical Monitor

Public contact point

Organisation

Jazz Pharmaceuticals Ireland Limited

Contact name

Medical Monitor

Third parties 19

Locations

1 EU/EEA country · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications