Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab, or trastuzumab + pertuzumab, or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen); therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial
Receipt of trastuzumab or ado-trastuzumab emtansine within 4 weeks of scheduled C1D1 dosing.
Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity
Patients with a history of LVEF decline to below 50% during or after prior trastuzumab or other HER2 directed therapy
Patients with a history of intolerance to trastuzumab (i.e. a grade 3 or 4 infusion reaction) are excluded; Note: patients with a history of mild infusion reaction to trastuzumab who have previously been successfully re-challenged after an infusion reaction with or without prophylactic medication are allowed
trastuzumab in case of HER2-positive
Patients may have received prior trastuzumab therapy alone or in combination with chemotherapy; a 2 week washout period is required between trastuzumab treatment and first dose of afatinib
For patients with MBC, prior adjuvant chemotherapy and trastuzumab more than or equal to 12 months prior to enrollment are allowed
LVEF < 50% during previous trastuzumab therapy
Completed single-agent trastuzumab emtansine or combination trastuzumab emtansine treatment in the parent study or who continue to receive single-agent trastuzumab emtansine or combination trastuzumab emtansine treatment at the time of the parent study closure and received the last study drug dose within the 6 weeks (42 days) prior to the first dose of study therapy on the extension study or Continue to receive treatment in the control arm of study BO21976/TDM4450g (NCT00679341) at the time of the parent study closure if the participant received the last dose of control arm study drug within the 6 weeks (42 days) prior to the first dose of control arm study therapy in the extension study
Participants in the control arm from Study BO21976/TDM4450g whose disease progression has occurred during the transition interval between the parent study and this extension study may initiate trastuzumab emtansine treatment at the time of enrollment into study TDM4529g (NCT00781612)
Expectation by the investigator that the participant may continue to benefit from additional single-agent trastuzumab emtansine or combination trastuzumab emtansine treatment or Expectation of the investigator that the participant may continue to benefit from control arm treatment as given in study BO21976/TDM4450g and at the time of disease progression may benefit from single-agent trastuzumab emtansine treatment
AEs leading to single-agent trastuzumab emtansine or combination trastuzumab emtansine treatment discontinuation in the parent study
Progressive disease on single-agent trastuzumab emtansine or a trastuzumab emtansine-containing regimen during the parent study or before starting the extension study, with the exception of participants from study TDM4688g (NCT00943670) with early disease progression who went on to receive pertuzumab + trastuzumab emtansine treatment and have not experienced further disease progression on the combination regimen
History of receiving any investigational treatment or other systemic therapy directed at controlling cancer (e.g., chemotherapy, trastuzumab, etc.) since the participant's last study drug dose in the parent study
History of hypersensitivity with previous trastuzumab emtansine or any agent used with trastuzumab emtansine in the parent study, precluding further dosing
Combination Arm: hypersensitivity to trastuzumab
No known hypersensitivity to trastuzumab
INCLUSION - TREATMENT: Undergo neoadjuvant chemotherapy with a trastuzumab based regimen prior to surgery and plan for completion of one year of trastuzumab
If Her2 positive, must have received and have progressed or are intolerant to treatment with trastuzumab for metastatic or recurrent disease
Less than 6 months from the completion of last trastuzumab infusion
Any condition that would be a contraindication to receiving trastuzumab as described in the approved local label or a condition that would prevent treatment with the physician's choice of chemotherapy
Patients refractory to prior therapy with trastuzumab are eligible
Patients who discontinued prior trastuzumab or T-DM1 due to progressive or refractory disease are eligible for enrollment; patients who discontinued prior trastuzumab or T-DM1 due to intolerance however are not eligible for enrollment
Regimen B only (combination with trastuzumab): Subjects with advanced metastatic HER2+ solid tumors
Receipt of any biological therapy, chemotherapy, or radiation within 1 week of the Screening Visit and at least 3 weeks prior to Day 1, except for patients receiving maintenance trastuzumab.
History of infusion-related reactions and/or hypersensitivity to trastuzumab, (ado-)trastuzumab emtansine;
Left Ventricular Ejection Fraction (LVEF) < 50%, or a history of clinically significant decrease in LVEF during previous treatment with trastuzumab or (ado-)trastuzumab emtansine;
At the time of study enrollment, patients must have at least 4 months of adjuvant trastuzumab planned
Patients/subjects with HER2 positive tumor that have not been treated with trastuzumab prior to enrollment
Women of child bearing potential must agree to use of a highly effective method of contraception from the time of informed consent until 6 months after the last dose of ado-trastuzumab emtansine; men must agree to use a barrier method of contraception while on treatment and for 6 months after the last dose of ado-trastuzumab emtansine
Prior therapy with ado-trastuzumab emtansine (patients who had prior trastuzumab or other HER2 targeted agents are eligible)
Known hypersensitivity to any component of ado-trastuzumab emtansine
Patients with persistent LV dysfunction 90 days after discontinuation of trastuzumab
Trastuzumab treatment within the last 3 months
Patients are allowed to consent to PANGEA as long as they have received 2 months (4 doses) or less of FOLFOX (plus trastuzumab if HER2 amplified) chemotherapy
Patient receiving or planning to receive trastuzumab, trastuzumab with pertuzumab or ado-trastuzumab emtansine, for at least 3 months, alone or in combination with other systemic treatment or radiation
No more than two prior cytotoxic chemotherapeutic regimens for metastatic breast cancer; in addition, prior trastuzumab emtansine (TDM-1, Kadcyla) is allowed
Biologic therapy (including antibodies [other than trastuzumab], immune modulators, cytokines) within 4 weeks before the first dose of study treatment; Note: there is no washout period required for trastuzumab
Currently taking cytotoxic chemotherapy; however, patients receiving non-investigational hormone therapy, lapatinib, and/or trastuzumab are eligible provided these medicines are at a stable dose and were begun more than 30 days prior to the first IT injection
Initiation of immunotherapy (such as trastuzumab-Herceptin) in the 30 days before treatment; patients who have been on trastuzumab for at least 30 days prior to treatment with progressive or stable disease are permitted to enroll, but required to stay on trastuzumab for the duration of the study
Bisphosphonates, hormone modification therapy, and trastuzumab are permitted without restriction
Eligible subjects must have completed appropriate treatment for their primary disease and be off cytotoxic chemotherapy and any immunosuppressive agents such as systemic steroids for at least 30 days prior to enrollment; patients should continue trastuzumab monotherapy throughout the course of this protocol; concurrent hormonal and biphosphonate therapies are allowed
Patients with persistent LV dysfunction 90 days after discontinuation of trastuzumab
Trastuzumab treatment within the last 3 months
Prior or concurrent use of trastuzumab
Have received prior treatment with trastuzumab.
Patients may not be on any cytotoxic chemotherapy or hormonal treatment for breast cancer during protocol treatment; (trastuzumab is allowed in HER2 positive patients)
Patients who have never received trastuzumab
Prior treatment with trastuzumab
Patients must have received prior trastuzumab for > 2 month period before disease recurrence or recurrence or progression while on trastuzumab-based therapy
Up to four prior chemotherapy regimens and anti-HER2 agents in the metastatic setting allowed; patients must have progressed on trastuzumab based therapy and must have received ado-trastuzumab emtansine for metastatic breast cancer
Prior therapy with trastuzumab
Prior therapy:\r\n* No limit to prior therapies with last anti-cancer treatment >= 2 weeks from initiation of protocol-based therapy provided all toxicities (other than alopecia) have resolved to =< grade 1 or baseline; for lapatinib and intravenous (IV) trastuzumab and/or pertuzumab, no washout is required\r\n* Patients with prior whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) are eligible, provided that there are new lesions not previously treated by SRS and >= 4 weeks have passed since radiation\r\n* Patients with prior cranial surgery are eligible, provided that there is evidence of residual disease and/or progression of disease and >= 4 weeks have passed since surgery\r\n* Prior hormonal therapy for locally advanced or metastatic disease is allowed and can be continued, if everolimus is used in a combination with hormonal therapy, then, everolimus must be discontinued but hormonal therapy can be continued\r\n* Continuation of intravenous (IV) trastuzumab is allowed for those patients already on IV trastuzumab therapy, patients previously treated with intrathecal (IT) trastuzumab are allowed if there is evidence of progression as determined by treating physician and last dose administered is >= 4 weeks\r\n* Prior capecitabine therapy is allowed, provided >= 6 months have passed since the last dose of capecitabine
Patients receiving any concurrent anticancer therapy or investigational agents with the intention of treating gastric/GEJ cancer; previously received trastuzumab as part of a regimen in the metastatic setting with evidence of progression; 89Zr-trastuzumab use as imaging agent for 89Zr-trastuzumab PET permitted
Patients with prior trastuzumab treatment
participant must have received trastuzumab emtansine (T-DM1) in any disease setting
Unwillingness to discontinue ado-trastuzumab emtansine or lapatinib use
History of prior grade 3 or 4 hypersensitivity or any toxicity to trastuzumab that warranted permanent cessation of this antibody
Patients must have completed a course of prior adjuvant trastuzumab or experienced side effects that resulted in early discontinuation of trastuzumab that have since resolved
The last dose of trastuzumab must have been given >2 weeks and ?1 year (365 days) from enrollment
Part 2, Cohort 2: Histologically confirmed local laboratory testing (immunohistochemistry 3+ staining and/or fluorescence in situ hybridization ratio >= 2.0) HER2+ metastatic breast cancer subjects who are resistant to trastuzumab-containing treatment and progressed on trastuzumab, pertuzumab, a taxane, and/or trastuzumab emtansine. There is no limit regarding the number of prior lines of therapy. Subjects may be enrolled regardless of whether or not their tumor harbors a PAM pathway alteration (documentation of PAM pathway alteration for this cohort is not required).
Chemotherapy, immunotherapy, biologic therapy, or any other anticancer therapy within 2 weeks (or five elimination half lives for noncytotoxics, whichever is shorter) of Day 1 of trial drug treatment (6 weeks for nitrosureas or mitomycin). Subjects on therapy with trastuzumab (trastuzumab cohort) may continue with trastuzumab during the screening phase of the study. Subjects on endocrine therapy may continue with antihormonal therapy until Day 1 of the study.
Patients with known HER-2 overexpressing MBC must have failed at least one prior trastuzumab-containing regimen for metastatic disease.
HER-2/neu negative or, if HER-2/neu positive, disease must have previously progressed on treatment with trastuzumab
Any prior treatment with T-DM1 (trastuzumab emtansine) or any trastuzumab therapy
HER-2/neu status known and participants with HER2/neu positive tumors show documentation of disease progression on treatment containing trastuzumab
Most recent treatment regimen for metastatic disease must include Trastuzumab and chemotherapy.
Note: Trastuzumab emtansine (T-DM1) is considered acceptable as prior Trastuzumab/chemotherapy regimen
Note: Discontinuation of Trastuzumab is not necessary.
Prior treatment with Trastuzumab in combination with Lapatinib or prior treatment with an irreversible inhibitor of the intracellular domain of the HER2 receptor such as neratinib
Patients must have had progression on a trastuzumab and/or taxane-based chemotherapy regimen: \r\n* Metastatic patients must have progressed during or after trastuzumab and/or taxane treatment (at any time)\r\n* Locally advanced patients must have progressed within 6 months after trastuzumab and/or taxane treatment \r\nNote: patients who had prior trastuzumab and/or taxane-based chemotherapy in the adjuvant setting only may still be eligible if, in the opinion of the treating investigator, the patient is not an appropriate candidate to receive trastuzumab/pertuzumab/docetaxel as a first-line regimen for their metastatic disease
Patients with a history of grade >= 3 hypersensitivity reaction to trastuzumab, OR grade >= 1 with the most recent trastuzumab infusion before study entry, OR continued requirement for prolonged trastuzumab infusions to prevent hypersensitivity reactions are not eligible for participation
Patients with a history of intolerance to trastuzumab and/or adverse events related to trastuzumab that resulted in trastuzumab being permanently discontinued are not eligible for participation
Previous therapy with any HER2 TKI (such as trastuzumab, lapatinib, neratinib, etc.) for any malignancy.
Previously received trastuzumab as part of a regimen in the perioperative or metastatic setting with evidence of progression; 89Zr-trastuzumab use as imaging agent for 89Zr-trastuzumab PET permitted
Patients who have previously provided samples at any time after trastuzumab resistance will be exempt from biopsy at the start of therapy
Patients receiving any concurrent anticancer therapy or investigational agents with the intention of treating esophagogastric cancer; 89Zr-trastuzumab uses as imaging agent for 89Zr-trastuzumab PET permitted
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, hormone treatment (with the exception of megestrol acetate), or concurrent radiotherapy is not allowed concomitantly with the administration of study treatment; 89Zr-trastuzumab use as imaging agent for 89Zr-trastuzumab PET permitted
Prior treatment with trastuzumab emtansine
One of the following subgroups of patients with HER2 overexpression as follows: \r\n* Histologically-confirmed breast cancer that is metastatic or locally recurrent (7th Edition of the American Joint Committee on Cancer [AJCC] Tumor, Lymph Node, Metastasis [TNM] System) and measurable and/or evaluable or non-measurable by RECIST 1.1 criteria with HER2/neu overexpression by immunohistochemistry (2+,3+) or fluorescent in situ hybridization (FISH)+ and progressive disease despite having received at least 1 prior Food and Drug Administration (FDA) approved HER2 targeted therapy (e.g. trastuzumab, trastuzumab plus pertuzumab, T-DM1, or lapatinib) (determined by their physician); prior therapy has at least one of the following stipulations: \r\n** Patients may have received neoadjuvant or adjuvant treatment with prior trastuzumab or lapatinib treatment \r\n** Patients have received a trastuzumab, trastuzumab + pertuzumab, or T-DM1-based therapy for locally advanced or metastatic disease for a minimum of 9 weeks duration; patients may have received more than 1 trastuzumab-based combination therapy\r\n** Patients have received a lapatinib-based therapy for locally advanced or metastatic disease for a minimum of 9 weeks duration; patients may have received more than 1 lapatinib-based combination therapy\r\n* Histologically-confirmed gastric, esophageal, or gastroesophageal adenocarcinoma that is metastatic or locally recurrent (7th Edition of the AJCC TNM System) and measurable or non-measurable by RECIST 1.1 criteria with HER2/neu overexpression by immunohistochemistry (2+,3+) or FISH+ and progressive disease despite having received at least 1 prior HER2 targeted therapy for a minimum of 9 weeks duration) (determined by their physician) or with previously documented HER2 over-expressing disease not being currently treated on a HER2 targeted therapy\r\n* Other histologically confirmed metastatic (stage IV) or locally recurrent (stage III) (7th Edition of the AJCC TNM System) malignancy with HER2/neu overexpression by immunohistochemistry (2+,3+) or FISH+; no prior HER2 directed therapy will be required for this subgroup; however, patients will been required to have at least 1 line of therapy with a known survival benefit for their malignancy
Disease progression while receiving adjuvant trastuzumab and/or lapatinib treatment
Subjects whose tumors overexpress ErbB2 are eligible provided that they have progressed following therapy which included trastuzumab and/or lapatinib:\r\n* Note for prior lapatinib: subjects must have completed therapy with lapatinib at least 7 days prior to the first dose of study drug\r\n* Note for prior trastuzumab: subjects who received thrice weekly (Q3 weekly), twice weekly (Q2 weekly) or once weekly (Q1 weekly) must have completed therapy with trastuzumab at least 3 weeks, 2 weeks or 1 week, respectively, prior to the first dose of study drug
No more than 4 prior chemotherapy regimens for metastatic disease for those in the dose escalation cohorts; prior trastuzumab and lapatinib are allowed for the HER2+ population; once we reach the expanded recommended phase 2 dose (RP2D) cohorts, patients enrolled must have received =< 3 prior regimens\r\n* Patients enrolled in ARM C may remain on trastuzumab without a washout period\r\n* Patients enrolled in ARM D may remain on lapatinib without a washout period
Prior treatment with lapatinib or trastuzumab are allowed, provided that the agents have never been given in combination
History of allergic reactions attributed to compounds of similar chemical or biological composition to lapatinib or trastuzumab; however, patients with a history of infusion reaction to trastuzumab which was controlled with premedication on subsequent infusions without a recurring infusion reaction are eligible
Prior use of Herceptin (trastuzumab), and a taxane
More than 2 prior Herceptin (trastuzumab) regimens or prior use of Xeloda (capecitabine) and / or Tykerb (lapatinib) [Tyverb]
Prior treatment with vinorelbine for metastatic setting, or prior treatment with any ErbB-2 targeted agents except trastuzumab (part 2 only). Up to 20 subjects with ErbB-2-overexpressing metastatic breast cancer who have been previously exposed to lapatinib but are not refractory to lapatinib may be enrolled in part 2.
For patients who are Her2 positive and will be treated on the trastuzumab + mDCF cohort, prior trastuzumab treatment is not allowed
For patients who are Her2 positive and will be treated on the trastuzumab + mDCF cohort, left ventricular function < 50%
Known history of positive serum human ADA to trastuzumab.
Patients must have progressed on, or be intolerant to ado-trastuzumab emtansine in the LABC/MBC setting
Patients who previously discontinued trastuzumab due to unacceptable cardiac toxicity
Patients with a history of LVEF decline to below 50% during or after prior trastuzumab/lapatinib or other HER2 directed therapy.
Subjects should have received and failed at least one prior cytotoxic chemotherapy regimen for advanced disease that included trastuzumab
Prior treatment with afatinib or any other HER2 inhibitor other than trastuzumab
Front-line chemotherapy that did not contain trastuzumab
Treated with ado-trastuzumab emtansine (T-DM1) Part 2b:
Treated with trastuzumab Part 2c:
Treated with ado-trastuzumab emtansine (T-DM1) (patients with HER2 overexpression only)
Prior treatment with trastuzumab emtansine, docetaxel, or paclitaxel either as single\n             agents or as part of a treatment regimen.
At least 2 weeks since prior radiotherapy, endocrine therapy, trastuzumab, or lapatinib, with complete recovery from the effects of these interventions
Completed 12 to 24 weeks of first- or second-line treatment with trastuzumab in combination with chemotherapy
Prior treatment with anti-HER2 therapy, except trastuzumab or lapatinib
Prior treatment with a trastuzumab containing chemotherapy regimen is required.
Currently receiving adjuvant trastuzumab (Herceptin)
Patients with Her2+ breast cancer receiving Her2-directed therapy (e.g. trastuzumab) may continue on that therapy when enrolling into a dose level for which safety has been established
No prior history of intolerance or hypersensitivity to trastuzumab and/or adverse events related to trastuzumab, murine proteins, or any of the excipients that resulted in trastuzumab being permanently discontinued
Trastuzumab =< 21 days before first study treatment
Any prior ado-trastuzumab emtansine
History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab treatment
Metastatic breast cancer patients must have received a minimum of 1 and a maximum of 3 prior anti HER2 based regimens with documented progression on the most recent regimen which must contain trastuzumab, ado-trastuzumab emtansine or lapatinib
Metastatic gastric cancer patients must have received a minimum of 1 and a maximum of 2 prior anti HER2 based regimens with documented progression on the most recent regimen which must contain trastuzumab or ado-trastuzumab emtansine
Patients must have at least one prior trastuzumab-containing regimen
Patients with HER2-positive disease must have progressed on or following trastuzumab
Prior therapy with lapatinib or an ErbB2 inhibitor other than trastuzumab (including but not limited to trastuzumab-DM1 and neratinib) and capecitabine;
Previous treatment with all of the following: lapatinib, and trastuzumab emtansine; (patients are eligible if treated with 3 or less of these agents)
Patients must have metastatic breast cancer and be initiating within 7 days of step 1 registration or continuing trastuzumab–based HER-2 targeted therapy without concurrent anthracyclines in first or second line setting; patients may have brain metastasis; there is no limit for number of doses of HER-2 targeted therapy prior to registration; examples of eligible HER-2 targeted therapy:\r\n* Trastuzumab\r\n* Trastuzumab + chemotherapy or hormonal therapy\r\n* Trastuzumab + other HER-2 targeted agent with or without chemotherapy (such as pertuzumab)\r\n* Ado-trastuzumab (Kadcyla)\r\n* NOTE: Patients on lapatinib without trastuzumab are not eligible; planned treatment with concurrent HER-2 targeted therapy and anthracyclines is not permitted
Eligible after 2 months of completing all their active cancer treatment with the exception of long-term hormonal treatments or trastuzumab.
Scheduled to receive adjuvant or neoadjuvant trastuzumab therapy            \r\n* Anthracycline-containing regimens allowed\r\n* Patients receive trastuzumab with their chemotherapy allowed for eligibility work-up\r\n* Taxanes are allowed\r\n* Trastuzumab therapy may be given with or after primary chemotherapy
No prior trastuzumab or anthracyclines prior to this chemotherapy regimen
Scheduled to receive adjuvant therapy consisting of doxorubicin followed by trastuzumab
Completed an approved regimen of neoadjuvant or adjuvant therapy with an approved regimen that includes trastuzumab and at least four cycles (12 weeks) of taxane-containing chemotherapy with plan for completion of one year of trastuzumab therapy.
Completion of chemotherapy or trastuzumab for > six months and of radiation therapy for >= 2 months, as applicable and 2 years or less from completion of standard therapy
Women who have received cancer surgery, chemotherapy, biological therapy (e.g., trastuzumab), or radiotherapy for the treatment of any cancer within 6 months of study participation
Prior trastuzumab therapy
Patients with known sensitivity or contraindication to any of the component of 89Zr-DFO-trastuzumab (89Zr or desferrioxamine [DFO] or trastuzumab)
Patients who have received trastuzumab must have at least a washout period for trastuzumab of 14 days, this will not apply to 89Zr-DFO-trastuzumab repeat, post treatment assessment where patients may be receiving trastuzumab
Patients who may not have received trastuzumab within the prior 6 months for any other reason
Patients may not have received trastuzumab within 6 weeks of projected 64Cu-DOTA-trastuzumab/PET-CT
Participants who have received trastuzumab within the prior 36 days
Participants who are not considered candidates for ado-trastuzumab-emtansine
May continue ongoing trastuzumab therapy
At least 2 prior HER2-directed therapy regimens for metastatic breast cancer, including trastuzumab and TDM-1.