A Study of Poziotinib in Patients With Epidermal Growth Factor Receptor (EGFR) or Human Epidermal Growth Factor Receptor 2 (HER2) Activating Mutations in Advanced Malignancies

Phase 2

Terminated

Conditions: Breast Cancer
Colorectal Cancer
Solid Tumor
Glioblastome Multiforme

Interventions: Drug: Poziotinib Hydrochloride
Drug: Loperamide

Registration Number: NCT04172597

Lead Sponsor: Spectrum Pharmaceuticals, Inc

Brief Summary: This is a Phase 2, open-label, multicenter study whose principal objectives are to evaluate the efficacy and safety/tolerability of poziotinib in five cohorts of 30 previously-treated patients each.

Detailed Description: The Screening period (Day -30 to Day 1) begins 30 days prior to poziotinib treatment on Day 1 of Cycle 1. Patients must meet all Inclusion/Exclusion Criteria and provide informed written consent prior to study procedures.

The duration of each treatment cycle is 28 days. There will be five patient cohorts. Eligible patients will be enrolled into cohorts concurrently based on EGFR or HER2 exon 20 mutation status.

* Cohort 1: HER2-positive or HER2-negative breast cancer (BC) with a HER2 activating mutation.

* Cohort 2: Colorectal cancer (CRC) with a HER2 activating mutation.

* Cohort 3: Any solid cancer, except non-small cell lung cancer (NSCLC), BC, or CRC with a HER2 activating mutation.

* Cohort 4: Glioblastome multiforma (GBM) with an EGFR activating mutation.

* Cohort 5: Any solid cancer, except NSCLC or GBM with an EGFR activating mutation.

All patients will be treated daily for up to 24 months unless there is disease progression, death, intolerable adverse events (AEs), or another protocol-specified reason for patient withdrawal. After treatment discontinuation, patients will be contacted every 3 months for up to 2 years after the first dose of poziotinib to assess survival.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 1

Inclusion Criteria

Patients must be at least 18 years old.
Patients must have histologic or cytologic evidence of a malignant solid cancer that is either advanced or metastatic there must be no available therapy known to confer a reasonable likelihood of clinical benefit.
Patients with BC must have a HER2 activating mutation determined by next-generation sequencing (NGS) performed on either tumor or plasma samples and:
- Immunohistochemistry (IHC) HER2-positive BC that has progressed on trastuzumab, pertuzumab, and trastuzumab emtansine (T-DM1) in the metastatic setting, unless there is recurrent disease within 12 months of adjuvant or neoadjuvant treatment.
- IHC HER2-negative, estrogen receptor/progesterone receptor (ER/PR)-positive BC that has progressed on or after appropriate first-line endocrine therapy in the metastatic setting.
- IHC HER2-negative, ER/PR-negative BC that has progressed after first-line treatment (any standard chemotherapy-based regimen) in the metastatic setting.
Patients with microsatellite instability-high (MSI-H) CRC must have had appropriate checkpoint inhibitor-based therapy.
Patient's tumor must be positive for an EGFR or HER2 mutation based on DNA testing of either tumor tissue or plasma samples. Patients with documented EGFR or HER2 mutations may be identified by local testing from participating sites using next generation sequencing tests. Patient has a solid tumor with at least one of the listed activating mutations:
- Cohorts 1-3: HER2 Activating Mutations (at least one of the following) Furin-Like/Extracellular. S310F/Y Transmembrane. I655V, V659E, R678Q, V697L Kinase Domain. Exon 20 insertion, T733I, L755X, I767M, D769X, V773M, V777X, L786V, V842I, T862I, L869R.
- Cohorts 4-5: EGFR Activating Mutations (at least one of the following) Extracellular & Transmembrane: EGFRvIII, R108K, R222C, A289T, P596L, G598V Kinase Domain: Exon 20 insertion, E709X, E709_T710del insD, L718X, G719X, I740_K745dupIPVAIK, I740_K745dup, V742I, L747X, E746_A750del, A750P, S768I, S768I/V769L, S768I/V774M, L833V, V769M, V774M, R831C, R831H, L858R, L861Q, A864V.
Patients must have measurable disease.
Patients with central nervous system (CNS) metastases must have stable CNS disease and no evidence of growth on imaging for at least 4 weeks following radiation or other locoregional ablative therapy. CNS symptoms must be stable with no requirement for anti-seizure medications and/or > 2 mg/day dexamethasone equivalent, except for patients with GBM (Cohort 4), in whom anti-seizure medications and/or up to 4 mg/day dexamethasone equivalent is allowed.
Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ -1.
Patients must have adequate hematopoietic, renal, and liver functions.

Exclusion Criteria

Patient has an EGFR T790 mutation.
Patient has breast or gastric cancer without eligible HER2 mutations (see Inclusion Criteria).
Patients with GBM enrolled in Cohort 4 has been treated with an inhibitor of vascular endothelial growth factor (VEGF) inhibitor therapy (e.g., bevacizumab).
Patient requires treatment with a medication that is a strong inhibitor or inducer of CYP3A4 or CYP2D6 or has been treated with such medications within 15 days of poziotinib treatment.
Patient has ≥ Grade 2 skin disorders (rash), mucositis, or stomatitis within 15 days of poziotinib treatment.
Patient has a gastrointenstinal disorder or malabsorption that precludes oral drug treatment.
Patient has active liver or biliary tract disease (except for Gilbert's syndrome, asymptomatic biliary stones, liver metastasis, or stable chronic liver diseases).
Patient has a history of drug-induced pancreatitis.
Patient has a history of interstitial lung disease or pneumonitis.
Patient has a history of congestive heart failure Class III/IV according to the New York Heart Association Functional Classification or a serious cardiac arrhythmia requiring treatment.
Patient has a high risk of cardiac disease as determined by the Investigator. If patient is deemed to have a high cardiac risk, enrollment may be considered if an echocardiogram (ECHO) or multi-gated acquisition (MUGA) during Screening demonstrates a cardiac ejection fraction >= 50%.
Patient has a QTc interval > 470 ms.
Patient has a history of another malignancy within the 1 year prior to poziotinib treatment. Patients with the following concomitant neoplastic diagnoses are eligible: non-melanoma skin cancer, carcinoma in situ (including transitional cell carcinoma, cervical intraepithelial neoplasia, and melanoma in situ), organ-confined prostate cancer with no evidence of progressive disease.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cohort 3	Poziotinib Hydrochloride	Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 2	Poziotinib Hydrochloride	Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 1	Poziotinib Hydrochloride	Patients with HER2-positive or HER2-negative BC with a HER2 activating mutation will receive poziotinib 8 milligrams (mg), orally, twice daily (BID) starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 4	Poziotinib Hydrochloride	Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 5	Poziotinib Hydrochloride	Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 1	Loperamide	Patients with HER2-positive or HER2-negative BC with a HER2 activating mutation will receive poziotinib 8 milligrams (mg), orally, twice daily (BID) starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 2	Loperamide	Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 3	Loperamide	Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 4	Loperamide	Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.
Cohort 5	Loperamide	Patients with CRC with a HER2 activating mutation will receive poziotinib 8 mg, orally, BID starting on Day 1 of each 28 day cycle for up to 24 months unless there is disease progression, death, intolerable AEs, or another protocol-specified reason for participant withdrawal. Loperamide may be prescribed for the treatment of diarrhea as needed.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR)	Up to 168 days	ORR was defined as the percentage of participants with confirmed complete response (CR) and partial response (PR) as assessed by the investigator using local radiology evaluation according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR.

Secondary Outcome Measures

Name	Time	Method
Disease Control Rate (DCR)	Up to 168 days	DCR is defined as percentage of participants with best response of CR, PR, and stable disease (SD) from the first dose of poziotinib to the end of study. CR is defined as disappearance of all target and non-target lesions. Any pathological lymph nodes must have reduction in short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter (LD) since the treatment started.
Duration of Response (DoR)	Up to 168 days	Duration of response was defined as the time from the date that measurement criteria are first met for CR or PR until the first subsequent date that progressive disease or death is documented. CR is defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes must have a reduction in the short axis to \<10 mm. PR is defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Disease progression (PD) is defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions.
Percentage of Participants With AE	Up to 30 days after last dose of study drug (Up to 199 days)	An AE is defined as any untoward medical occurrence in a patient or clinical investigation patient, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Therefore, an AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product.