Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers

Sponsor

Zymeworks Inc. (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02892123

Collaborator

(none)

279

Enrollment

Locations

Arm

Duration (Months)

16.4

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a first-in-human, 3-part study to investigate the safety, tolerability, and effectiveness of ZW25 (zanidatamab) by itself and combined with selected chemotherapy agents in patients with locally advanced (unresectable) and/or metastatic human epidermal growth factor receptor 2 (HER2)-expressing cancers. This study will also the evaluate the way the body absorbs, distributes, and eliminates ZW25 (pharmacokinetics or PK).

Condition or Disease	Intervention/Treatment	Phase
HER2-expressing Cancers	Drug: ZW25 (Zanidatamab) Drug: Paclitaxel Drug: Capecitabine Drug: Vinorelbine Drug: Tucatinib Drug: Tucatinib	Phase 1

Detailed Description

Part 1 of the study will evaluate increasing doses of ZW25 to find the highest dose of ZW25 that does not cause unacceptable side effects (maximum-tolerated dose or MTD), the lowest safe dose with the highest rate of effectiveness (optimal biological dose or OBD), and/or other recommended dosages (RDs) of ZW25 in up to 7 dose-specific cohorts. Eligible patients include those with selected HER2-expressing locally advanced (unresectable) and/or metastatic cancers that have progressed after receipt of all therapies known to confer clinical benefit (or ineligible to receive therapy).

Part 2 of the study will further evaluate the safety, tolerability, and efficacy of ZW25 in patients with selected HER2-expressing locally advanced (unresectable) and/or metastatic cancers that have progressed after receipt of all therapies known to confer clinical benefit (or ineligible to receive therapy) in up to 5 separate disease-specific cohorts.

Part 3 of the study will evaluate the safety, tolerability, and efficacy of ZW25 combined with selected chemotherapy agents, including paclitaxel, capecitabine, vinorelbine, or capecitabine and tucatinib. Patients with selected HER2-expressing locally advanced (unresectable) and/or metastatic cancers that have progressed after at least 1 and no more than 3 prior systemic chemotherapy regimens will be evaluated in this part of the study.

Study Design

Study Type:

Interventional

Actual Enrollment :

279 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Trial of ZW25 in Patients With Locally Advanced (Unresectable) and/or Metastatic HER2-expressing Cancers

Study Start Date :

Sep 1, 2016

Anticipated Primary Completion Date :

Sep 1, 2022

Anticipated Study Completion Date :

Oct 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ZW25 (Zanidatamab) Monotherapy and ZW25 Combination Therapy	Drug: ZW25 (Zanidatamab) ZW25 administered IV once weekly, once every 2 weeks, or once every 3 weeks. Part 1: in multiple increasing doses; Part 2: ZW25 given at the MTD, OBD, or an RD identified in Part 1; Part 3: ZW25 given at the MTD, OBD, or an RD combined with one of the following selected drug combination: Drug: Paclitaxel Combination therapy with ZW25 - Part 3 Treatment Groups 1 and 4 Drug: Capecitabine Combination therapy with ZW25 - Part 3 Treatment Groups 2 and 5 Drug: Vinorelbine Combination therapy with ZW25 - Part 3 Treatment Groups 3 and 6 Drug: Tucatinib Combination therapy with ZW25 and Capecitabine - Part 3 Treatment Group 7 Drug: Tucatinib Combination therapy with ZW25 - Part 3 Treatment Group 8 (may be opened if recommended by the Safety Monitoring Committee and/or the sponsor)

Arm

Intervention/Treatment

Experimental: ZW25 (Zanidatamab) Monotherapy and ZW25 Combination Therapy

Drug: ZW25 (Zanidatamab)

ZW25 administered IV once weekly, once every 2 weeks, or once every 3 weeks. Part 1: in multiple increasing doses; Part 2: ZW25 given at the MTD, OBD, or an RD identified in Part 1; Part 3: ZW25 given at the MTD, OBD, or an RD combined with one of the following selected drug combination:

Drug: Paclitaxel

Combination therapy with ZW25 - Part 3 Treatment Groups 1 and 4

Drug: Capecitabine

Combination therapy with ZW25 - Part 3 Treatment Groups 2 and 5

Drug: Vinorelbine

Combination therapy with ZW25 - Part 3 Treatment Groups 3 and 6

Drug: Tucatinib

Combination therapy with ZW25 and Capecitabine - Part 3 Treatment Group 7

Drug: Tucatinib

Combination therapy with ZW25 - Part 3 Treatment Group 8 (may be opened if recommended by the Safety Monitoring Committee and/or the sponsor)

Outcome Measures

Primary Outcome Measures

The proportion of patients who experience dose-limiting toxicities (DLTs) (Part 1) [Up to 8 months]
The proportion patients who experience laboratory abnormalities and/or adverse events as defined by CTCAE v4.03 that are related to treatment (Parts 2 and 3) [Throughout the duration of the study; up to 2 years]

Secondary Outcome Measures

Serum concentrations of ZW25 [Throughout the duration of the study; up to 2 years]
The proportion of patients who develop detectable anti-drug antibodies [Throughout the duration of the study; up to 2 years]
The proportion of patients with an objective response (partial response or complete response) as defined by RECIST 1.1 criteria [Throughout the duration of the study; up to 2 years]
Progression free survival as defined by RECIST 1.1 criteria [Throughout the duration of the study; up to 2 years]
The proportion patients who experience laboratory abnormalities and/or adverse events as defined by CTCAE v4.03 that are related to treatment (Part 1) [Throughout the duration of the study; up to 2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

HER2-expressing cancer as follows:

Part 1:

Cohorts 1 - 3: Any locally advanced (unresectable) and/or metastatic HER2-expressing (HER2 1+, 2+, or 3+ by IHC) cancer (including but not limited to breast, gastric, ovarian, colorectal and non-small cell lung) that has progressed after receipt of all therapies known to confer clinical benefit
Cohort 4:
HER2 IHC 2+ /FISH- breast cancer or gastroesophageal adenocarcinoma (GEA)
HER2 IHC 3+ or HER2 IHC 2+ /FISH+ breast cancer or GEA
Any other HER2 IHC 3+ or FISH+ cancer
HER2-overexpressing (3+ by IHC) or HER2-2+ and FISH+ breast cancer must have progressed after prior treatment with trastuzumab, pertuzumab, and T-DM1
HER2-overexpressing (3+ by IHC) or HER2-2+ and FISH+ GEA must have progressed after prior treatment with trastuzumab
Patients with colorectal cancer must be KRAS wild-type
Patients with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion negative as determined by standard methods
Cohorts 5 - 6: HER2 IHC 3+ or HER2 IHC 2+ /FISH+ GEA must have progressed after prior treatment with trastuzumab
Cohort 7 (only at selected sites): HER2 IHC 3+, HER2 IHC 2+ /FISH+, or HER2 IHC 2+ /FISH- breast cancer must have progressed after prior treatment with trastuzumab, pertuzumab, and T-DM1

Part 2:

Locally advanced (unresectable) and/or metastatic cancer that has progressed after receipt of all therapies known to confer clinical benefit (unless ineligible to receive a specific therapy) as follows:

Cohort 1: HER2 IHC 2+/FISH- breast cancer
Cohort 2: HER2 IHC 3+ or HER2 IHC 2+/FISH+ breast cancer
Cohort 3: HER2 IHC 2+/FISH- GEA
Cohort 4: HER2 IHC 3+ or HER2 IHC 2+/FISH+ GEA
Cohort 5: Any other HER2 IHC 3+ or IHC 2+/FISH+ cancer, including the following:
Cohort 5a: HER2 IHC 3+ or IHC 2+/FISH+ GI cancers other than GEA (patients with colorectal cancer must be KRAS wild-type.)
Cohort 5b: Any other HER2 IHC 3+ or IHC 2+/FISH+ solid tumor types that are not breast or GI cancers (patients with NSCLC must have ALK wild-type, EGFR wild-type, and ROS1 fusion negative as determined by standard methods; patients with ovarian cancers must be KRAS wild type.)

Part 3:

Locally advanced (unresectable) and/or metastatic cancer as follows:

HER2 IHC 1+ or IHC2+/FISH- breast cancer patients (TGs 1, 2, or 3) who have received at least 1 and no more than 3 prior systemic chemotherapy regimens
HER2 IHC 3+ or IHC 2+/FISH+ breast cancer patients (TGs 1, 2, or 3) who have received prior therapy with trastuzumab, pertuzumab, and T-DM1, at least 1 and no more than 3 prior systemic chemotherapy regimens
HER2 IHC 2+ or 3+ FISH+ or FISH- GEA patients (TGs 1 or 2) who have received at least 1 and no more than 3 prior systemic chemotherapy regimens
HER2 IHC 3+ or IHC 2+/FISH+ GEA patients who have received prior therapy with trastuzumab (TG4; ZW25 + paclitaxel)
HER2 IHC 3+, IHC 2+/FISH+ or otherwise HER2-positive per ASCO/CAP guidelines breast cancer patients who have received prior therapy with trastuzumab, pertuzumab, and T-DM1 (TG5; ZW25 + capecitabine)
HER2 IHC 3+, IHC 2+/FISH+ or otherwise HER2-positive per ASCO/CAP guidelines breast cancer patients (TG6) who have received prior therapy with trastuzumab, pertuzumab, and T-DM1
HER2 IHC 3+, IHC2+/FISH+, or otherwise HER2-positive per ASCO/CAP guidelines breast cancer patients (TG7) who have received prior therapy with trastuzumab, pertuzumab, and T-DM1
HER2 IHC 3+, IHC 2+/FISH+, or otherwise HER2-positive per ASCO/CAP guidelines breast cancer patients (TG8) who have received prior therapy with trastuzumab, pertuzumab, and T-DM1

≥ 18 years of age
ECOG performance status of 0 or 1
Life expectancy of at least 3 months per the investigator's assessment.
Adequate organ function
Adequate cardiac left ventricular function, as defined by a LVEF >/= institutional standard of normal
For Part 1 Cohorts 1 - 3: evaluable disease (target or non-target lesions) per RECIST version 1.1. For Part 1 Cohorts 4 - 7, and Parts 2 and 3: measurable disease (target lesions) per RECIST version 1.1
Able to provide tumor sample (fresh or archived)
For Part 3 TGs 7 and 8 only - based on screening brain MRI, patients must have one of the following:

No evidence of brain metastases
Untreated brain metastases not needing immediate local therapy. For patients with untreated CNS lesions > 2.0 cm on screening contrast brain MRI, discussion with and approval from the medical monitor is required prior to enrollment
Previously treated brain metastases that are either stable since treatment or have progressed since prior local CNS therapy, provided there is no clinical indication for immediate re-treatment with local therapy in the opinion of the investigator

Exclusion Criteria:

Experimental therapies within 4 weeks before first ZW25 dosing
Treatment with other cancer therapy not otherwise specified within 4 weeks before ZW25 dosing
Anthracyclines within 90 days before first ZW25 dosing or lifetime load exceeding 300 mg/m² adriamycin or equivalent
Trastuzumab, pertuzumab, lapatinib, or T-DM1 within 3 weeks before first ZW25 dosing
Patients in Part 3 TG4 must not have received prior taxanes
Patients in Part 3 TG5 must not have received prior capecitabine for metastatic disease or received any prior fam-trastuzumab deruxtecan-nxki (DS-8201a)
With the exception of Part 3 TGs 7 and 8, untreated brain metastases (patients with treated brain mets who are off steroids and are stable for at least 1 month at the time of screening are eligible)
Pregnant or breast-feeding women
History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation
Acute or chronic uncontrolled renal disease, pancreatitis or liver disease (with exception of patients with Gilbert's Syndrome, asymptomatic gall stones, liver metastases, or stable chronic liver disease per investigator assessment)
Peripheral neuropathy > Grade 2
Clinically significant interstitial lung disease
Known active hepatitis B or C or known infection with HIV
Immunosuppressive corticosteroids equivalent to > 15mg/day of prednisone within 2 weeks before first ZW25 dose
QTc Fridericia (QTcF) > 450 ms
Having clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic CHF
Having known myocardial infarction or unstable angina within 6 months before first ZW25 dosing
Patients in Part 3 TG7 must not have received prior capecitabine or tucatinib for metastatic disease
Patients in Part 3 TG8 must not have received prior tucatinib therapy for metastatic disease

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35294
2	USC/Norris Cancer Center	Los Angeles	California	United States	90033
3	Hoag Family Cancer Institute	Newport Beach	California	United States	92663
4	University of Colorado Cancer Center	Aurora	Colorado	United States	80045
5	Rush University Medical Center	Chicago	Illinois	United States	60612
6	Sarah Cannon - Tennessee Oncology	Nashville	Tennessee	United States	37203
7	MD Anderson Cancer Center	Houston	Texas	United States	77030
8	South Texas Accelerated Research Therapeutics (START)	San Antonio	Texas	United States	78229
9	Northwest Medical Specialties	Tacoma	Washington	United States	98405
10	University of Ottawa	Ottawa	Ontario	Canada	K1H 8L6
11	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9
12	Jewish General Hospital	Montréal	Quebec	Canada	H3T1E2
13	Seoul National University Bundang Hospital	Seongnam-si	Gyeonggi-do	Korea, Republic of	13620
14	Seoul National University Hospital	Seoul		Korea, Republic of	03080
15	Severance Hospital	Seoul		Korea, Republic of	03722
16	Asan Medical Center	Seoul		Korea, Republic of	05505
17	Samsung Medical Center	Seoul		Korea, Republic of	06351