Clinical trial NCT02892123: Trial of ZW25 (Zanidatamab) in Patients With Advanced HER2-expressing Cancers
Official title: Phase I Trial of ZW25 in Patients With Locally Advanced (Unresectable) and/or Metastatic HER2-expressing Cancers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HER2-expressing Cancers
Keywords: HER2
Bispecific antibody
Biparatopic antibody
Immunotherapy
Breast cancer
Gastroesophageal adenocarcinoma (GEA)
Gastric cancer
Gastroesophageal junction (GEJ) cancer
Ovarian cancer
Non-small cell lung cancer (NSCLC)
Chemotherapy
Paclitaxel
Capecitabine
Vinorelbine
Tucatinib
Lead sponsor: Jazz Pharmaceuticals
Sponsor class: INDUSTRY
First posted: 2016-09-08
Enrollment: 279
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: Inclusion Criteria:

1. 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
2. ≥ 18 years of age
3. ECOG performance status of 0 or 1
4. Life expectancy of at least 3 months per the investigator's assessment.
5. Adequate organ function
6. Adequate cardiac left ventricular function, as defined by a LVEF \>/= institutional standard of normal
7. 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
8. Able to provide tumor sample (fresh or archived)
9. 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:

1. Experimental therapies within 4 weeks before first ZW25 dosing
2. Treatment with other cancer therapy not otherwise specified within 4 weeks before ZW25 dosing
3. Anthracyclines within 90 days before first ZW25 dosing or lifetime load exceeding 300 mg/m² adriamycin or equivalent
4. Trastuzumab, pertuzumab, lapatinib, or T-DM1 within 3 weeks before first ZW25 dosing
5. Patients in Part 3 TG4 must not have received prior taxanes
6. Patients in Part 3 TG5 must not have received prior capecitabine for metastatic disease or received any prior fam-trastuzumab deruxtecan-nxki (DS-8201a)
7. 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)
8. Pregnant or breast-feeding women
9. History of life-threatening hypersensitivity to monoclonal antibodies or to recombinant proteins or excipients in drug formulation
10. 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)
11. Peripheral neuropathy \> Grade 2
12. Clinically significant interstitial lung disease
13. Known active hepatitis B or C or known infection with HIV
14. Immunosuppressive corticosteroids equivalent to \> 15mg/day of prednisone within 2 weeks before first ZW25 dose
15. QTc Fridericia (QTcF) \> 450 ms
16. Having clinically significant cardiac disease such as ventricular arrhythmia requiring therapy, uncontrolled hypertension or any history of symptomatic CHF
17. Having known myocardial infarction or unstable angina within 6 months before first ZW25 dosing
18. Patients in Part 3 TG7 must not have received prior capecitabine or tucatinib for metastatic disease
19. Patients in Part 3 TG8 must not have received prior tucatinib therapy for metastatic disease

Primary outcomes:
measure: The proportion of patients who experience dose-limiting toxicities (DLTs) (Part 1)
timeFrame: Up to 8 months
measure: 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)
timeFrame: Throughout the duration of the study; up to 2 years
Secondary outcomes:
measure: Serum concentrations of ZW25
timeFrame: Throughout the duration of the study; up to 2 years
measure: The proportion of patients who develop detectable anti-drug antibodies
timeFrame: Throughout the duration of the study; up to 2 years
measure: The proportion of patients with an objective response (partial response or complete response) as defined by RECIST 1.1 criteria
timeFrame: Throughout the duration of the study; up to 2 years
measure: Progression free survival as defined by RECIST 1.1 criteria
timeFrame: Throughout the duration of the study; up to 2 years
measure: The proportion patients who experience laboratory abnormalities and/or adverse events as defined by CTCAE v4.03 that are related to treatment (Part 1)
timeFrame: Throughout the duration of the study; up to 2 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Los Angeles
country: United States
facility: USC/Norris Cancer Center
state: California
city: Newport Beach
country: United States
facility: Hoag Family Cancer Institute
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Nashville
country: United States
facility: Sarah Cannon - Tennessee Oncology
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics (START)
state: Texas
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: Ottawa
country: Canada
facility: University of Ottawa
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Gyeonggi-do
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
Study officials:
References:
citation: Meric-Bernstam F, Beeram M, Hamilton E, Oh DY, Hanna DL, Kang YK, Elimova E, Chaves J, Goodwin R, Lee J, Nabell L, Rha SY, Mayordomo J, El-Khoueiry A, Pant S, Raghav K, Kim JW, Patnaik A, Gray T, Davies R, Ozog MA, Woolery J, Lee KW. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol. 2022 Dec;23(12):1558-1570. doi: 10.1016/S1470-2045(22)00621-0. Epub 2022 Nov 16.