Breast Cancer

A Global, Interventional, Open-label Trial of T-DXd-based Therapy Followed by Palbociclib, Endocrine Therapy and Dual HER2 Blockade in First-line HER2+/HR+ Advanced or Metastatic Breast Cancer and Retreatment with T-DXd (DESTINY Breast Guide)

MOA: Trastuzumab deruxtecan (T-DXd) is a HER2 directed ADC with a topoisomerase I inhibitor payload.

Key Eligibility:

Inclusion Criteria-Upfront Treatment Phase

• Histologically confirmed HR+ and HER2+ la/MBC (local testing)
• No prior chemotherapy or HER2-targeted tx for MBC
  • If treated in (neo)adjuvant setting, pt are eligible if DFI >6 months from
    completion of systemic tx to PD
  • Previous T-DXd tx for eBC with an EFS or DFI of <12 months from
    completion of T-DXd tx in the neoadjuvant or post-neoadjuvant setting
    are excluded
• 1 prior line of ET tx for MBC is allowed
• Prior tx with any CDK inhibitor are excluded
• > 1 measurable lesion or non-measurable bone-only disease or lytic/mixed
  lytic bone lesions assessable by CT, MRI, or X-ray
• Asymptomatic brain metastases (<2 cm) or treated metastases that are no
  long symptomatic and requires no treatment are eligible
• Adequate treatment washout period before enrollment (check full protocol
  for details)

Inclusion Criteria- Maintenance Treatment phase

• No evidence of PD under T-DXd+P per RECIST v1.1 AND
• Pt willing to switch tx AND
• Completed at least 8 cycles of T-DXd+P and achieved cCR OR
• Completed 18 cycles (total) of T-DXd and achieved SD/PR and stable
  disease in last 2 scans) OR has unconfirmed CR
• Pt had no more than 24 cycles of tx with T-DXd+P

Inclusion Criteria- T-DXd Retreatment Phase

• Had received at least 1 dose of Maintenance Treatment
• Has PD per RECIST v1.1 per investigator assessment during Maintenance
  Treatment
• ILD/pneumonitis Grade ≥2 during the Upfront or Maintenance Treatment
  Phases are excluded
• Any unresolved SAE related to prior Maintenance Treatment Phase are
  excluded
• Non-ILD toxicities related to T-DXd in the Upfront Treatment Phase that
  required T-DXd discontinuation are excluded

A Randomized, Open-label Study Comparing the Bria IMT Regimen in Combination with Check Point Inhibitor vs Physician’s Choice in Metastatic Breast Cancer (BRIA-ABC)

MOA: A Randomized, Open-label Study Comparing the Bria IMT Regimen in Combination with Check Point Inhibitor vs Physician’s Choice in Metastatic Breast Cancer (BRIA-ABC)

Key Eligibility:

• MBC that have failed prior tx and have no meaningful alternative tx available
  • HER2+: ≥3 prior tx with ≥2 anti-HER2 and ≥1 chemotherapy regiment
  • ER+/PR+: refractory to hormonal tx (PD on ≥2 agents, in 2 separate lines)
  • TNBC: must have exhausted all curative intent tx including ≥2 prior chemo (neo and/or adjuvant settings)
  • Known germline/genomic actionable targets: must have had all tumor directed indicated tx
  • HER2-low: ≥HER2-targeted agent approved HER2-low in addition to any HR tx or germline/genomic actionable targets tx
  • HER2-negative: refractory to HR tx (if indicated) and had ≥2 prior chemotherapy
  • New or progressive BC metastatic to the brain are eligible if clinically stable, does not require steroid or had it discontinued ≥2 weeks prior to the first dose, and ≥3 weeks since surgical debulking before first dose
  • ECOG: 0-2

A Phase Ib/II Multicenter, Open-Label, Randomized Study Evaluating The Safety, Pharmacokinetics, And Activity, Of GDC-4198 Alone And In Combination With Giredestrant In Comparison With Abemaciclib In Combination With Giredestrant In Participants With Locally Advanced Or Metastatic Estrogen Receptor-positive, HER2-negative Breast Cancer Who Have Previously Progressed During Or After A CDK4/6 Inhibitor

MOA: GDC-4198 is a CDK4/2 inhibitor, developed to address the key resistance mechanism to CDK4/6 inhibitors.

Key Eligibility:

• ER+ (≥ 1%), HER-negative (local testing) LA or MBC
• PD on/after tx with CDK4/6 inhibitor and ET in the LA/MBC
  setting
  • More than 1 line of tx for LA/MBC are excluded
  • Prior chemotherapy for MBC excluded
  • Tx with approved oral ET within 7 days prior to initiation of study
    drug or tx with fulvestrant/approved CDK4/6 inhibitor within 21
    days prior to initiation of study drug are excluded
• Measurable/non-measurable evaluable (including bone only)
  disease per RECIST v1.1
• Most recent collected and representative tumor tissue must be
  provided
• Known and untreated or active CNS metastases are excluded

A Phase III, multisite, randomized, double-blind trial of BNT327 in combination with chemotherapy versus placebo with chemotherapy in patients with previously untreated locally recurrent inoperable or metastatic TNBC determined ineligible for PD-(L)1 therapy based on PD-L1 negative disease (ROSETTA Breast-01)

MOA: BNT327 (pumitamig) is a bispecific antibody that targets PD-L1 and VEGF-A.

Key Eligibility:

• Confirmed metastatic TNBC (ER/PgR <1%), or ER-low (1
  10%), HER2-negative (IHC 0, 1+ or 2+/FISH-) BC
  • ER-low, HER2- must be ineligible for ET-based tx
• PD-L1 negative based on local PD-L1 IHC 22C3 pharmDx
  assay on tissue from metastatic biopsy
• No prior systemic tx (including immunotherapy/ET) in the LA
  unresectable/metastatic setting
  • Prior tx with PD-(L)1/VEGF bispecific antibody excluded
• Pts who had (neo)adjuvant tx for Stage I-III BC must be ≥6
  months from completion of treatment to recurrence
• At least 1 measurable lesion per RECIST v1.1
• Tumor tissue from a metastatic site required at screening
• Treated stable brain metastases are allowed

A Study to Evaluate the Safety and Tolerability of the Covalent Phosphoinositide-3-Kinase (PI3K) alpha Inhibitor, TOS-358, in Adult Subjects with Select Solid Tumors

MOA: TOS-358 is a covalent inhibitor of WT and mutant PI3Kα and has much better toxicity profile compared to other inhibitors in this class

Key Eligibility:

• HR+/HER2- LA/rec or MBC with PIK3CA mutations (central testing) and
  measurable disease per RECIST v1.1
  • Response evaluable disease allowed
  • Tumor tissue must be provided for detection of PIK3CA mutation by central
    testing. Blood samples might be acceptable upon sponsor approval
• Must have received CDK4/6i in the adjuvant or metastatic setting or must be
  able to receive it on protocol AND
• Must not have received any prior chemotherapy (including ADC) in the
  metastatic setting AND
• No more than 3 prior lines of tx in total in the metastatic setting
• Prior PI3Kα inhibitor is allowed
  • If pt had PD on PI3K inhibitor, tissue or liquid biopsy submission following
    PD or at screening is required to verify resistance mutation(s)
• Pt receiving SERD at the time of consent may remain on it while receiving
  study tx.
• Pt may remain on CDK4/6i if enrolling to Phase 1b breast cancer group 2
• PTEN mutation or deletions and AKT activating mutations are excluded

An Interventional, Open-Label, Randomized, Multicenter, Phase 3 Study of PF-07248144 Plus Fulvestrant Compared to Investigator’s Choice of Therapy in Adult Participants with Hormone Receptor-Positive, HER2-Negative Advanced/Metastatic Breast Cancer Whose Disease Progressed After Prior CDK4/6 Inhibitor-based Therapy

MOA: PF-07248144 is a KAT6A inhibitor

Key Eligibility Criteria:

• HR+ /HER2-negative (IHC 0/1+, IHC 2+ & ISH-) LA/met BC
• Must have had prior CDK4/6i + ET (adv/met setting) OR adjuvant CDK4/6i + ET
  with documented PD/recurrence <12 months after last dose of CDK4/6i
• Must have had 1 prior systemic tx:
  • ET monotherapy in adv/met OR
  • Rechallenge tx with CDK4/6i + ET adv/met OR
  • Targeted therapy for ESR1 or BRCA1/2
  • Prior fulvestrant/exemestane is allowed but not required
  • Prior chemo, including ADCs, in adv/met setting are excluded
• >2 prior lines of systemic tx in adv/met setting are excluded
• Measurable disease or bone only disease by RECIST v1.1
• Tissue alterations in PIK3CA/AKT1/PTEN (local F1CDx assay) are excluded
  • Prior target tx for 1 or more of these alterations are excluded
• FFPE tumor tissue must be provided
• Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis or
  leptomeningeal disease excluded

A phase 3 randomized, double-blind, active-controlled study of palazestrant with ribociclib versus letrozole with ribociclib for the first-line treatment of ER+, HER2 advanced breast cancer (OPERA-02) OP-1250-302

MOA: Palazestrant (OP-1250) is an oral complete estrogen receptor antagonist (CERAN) and a selective estrogen receptor degrader (SERD)

Key Eligibility Criteria:

• Confirmed ER+ (≥1%) /HER2-negative MBC and one of the below:
  • de novo MBC (including recurrent BC in pts who didn’t receive adj ET)
  • Disease recurrence after 12 months of completing adj ET (± CDK4/6i)
• Patients with recurrence during adjuvant ET received for at least 24 months are excluded
• ≥1 measurable lesion per RECIST v1.1 or ≥1 lytic or lytic/blastic bone lesion evaluable by CT/MRI
• Prior tx with fulvestrant, elacestrant or any other investigational ET, in any setting, are excluded
• Currently/prior anti-cancer tx (ET, targeted tx, chemo, ADC) for ER+/HER2- MBC are excluded
• Known active/symptomatic CNS metastases, carcinomatous meningitis, leptomeningeal disease or spinal cord compression are excluded

CTC-EXPRESS: A Prospective Observational Study for CTC Expression and cfDNA/RNA Assessment in Metastatic Breast Cancer

Brief Summary: The purpose of this research is to learn if the CellSearch Circulating Tumor Cells (CTC) test can help doctors in making decisions about treatment and monitoring of breast cancer. The test consists of diagnostic CTC counts (enumeration) and expression of biomarkers Human Epidermal growth factor Receptor 2 (HER2), Estrogen Receptor (ER), and programmed death-ligand 1 (PD-L1) and cell free DNA/RNA (cfDNA/RNA) analysis.

Key Eligibility Criteria:

• Invasive breast cancer with radiographic and/or clinical evidence of advanced metastatic or unresectable disease.
• HR+/HER2 negative or triple negative (TN) subjects prior to starting first line therapy or beyond in the metastatic setting.
• OR HER2+ subjects prior to starting second line therapy or beyond in the metastatic setting.
  • Subject must have the CTC HER2, ER, PD-L1, and cfDNA/RNA tests ordered during routine patient care.
• Participant is pregnant excluded.
• Inability to provide blood samples based on the judgment of the treating physician excluded.

A randomised, open-label, phase III study of saruparib (AZD5305)
plus camizestrant compared with physician’s choice CDK4/6 Inhibitor
plus endocrine therapy or plus camizestrant for the first-line treatment
of patients with BRCA1, BRCA2, or PALB2 mutations and hormone
receptor-positive, HER2-negative (IHC 0, 1+, 2+/ ISH non-amplified)
advanced breast cancer (EvoPAR-Breast01)

MOA: Saruparib (AZD5305) is a selective inhibitor of PARP1, with minimal effect on PARP2.

Camizestrant (AZD9833) is a next generation SERD with activity in both ESR1 mutant and WT settings.

Key Eligibility:

• HR-positive (ER ≥ 1%), HER2-negative (IHC 0/1+ or IHC 2+/ ISH-) based
  on local testing
• LA/MBC with no prior systemic therapy in the advanced/metastatic
  setting
  • ET is allowed up to 28 days before C1D1
• Participants must have BRCA1/2 or PALB2 loss of function mutation prior
  to screening, either germline/tumor tissue (local testing)
  • FFPE tumor tissue must be provided for prospective central confirmation
• Pre/peri-menopausal women and males must be on an LHRH agonist
• At least 1 measurable and/or non-measurable lesion that can be accurately
  assessed at baseline and is suitable for repeated assessment as per
  RECIST v1.1
• Disease progression ≤84 days following (neo)adj tx for EBC excluded
• Disease progression ≤1 year from last dose of PARPi, platinum-agent,
  CDK4/6i, or oral SERD for EBC excluded

Phase 2, randomized, multicenter, open-label neoadjuvant study evaluating zanidatamab in combination with chemotherapy in participants with HER2-positive breast cancer (EmpowHER 208)

MOA: Zanidatamab is a HER2-targeted bispecific antibody against ECD2 and ECD4 domains of HER2

Key Eligibility:

• Stage II or III, tumor ≥2 cm, histologically confirmed BC
  • Inflammatory BC (T4d) are eligible
  • Bilateral BC excluded
• Known HR status, HER2+
  • HER2+ (IHC3+): randomized directly, with retrospective
    central confirmation
  • HER2+ (IHC2+ and ISH+): central confirmation prior to
    randomization
• Pt must be treatment naïve and not be planning to receive
  concurrent tx while on trial
• Pt must agree to undergo mastectomy or BCS after neoadj tx
  • Pt should undergo surgery 2-8 weeks following the last dose of neoadjuvant tx

A Phase 3, Randomized, Open-Label, Multicenter, Controlled Study To
Evaluate The Efficacy And Safety Of Zanidatamab In Combination With
Physician’s Choice Chemotherapy Compared To Trastuzumab In
Combination With Physician’s Choice Chemotherapy For The Treatment
Of Participants With Metastatic HER2-Positive Breast Cancer Who Have
Progressed On, Or Are Intolerant To, Previous Trastuzumab Deruxtecan
Treatment (EmpowHER 303)

MOA: Zanidatamab is a bispecific antibody targeting two distinct HER2 epitopes, ECD2 and ECD4.

Key Eligibility Criteria:

• Histologically confirmed HER2+ MBC (central testing)
  • Archived tissue or fresh biopsy must be submitted for HER2 central testing
    confirmation up to 12 months prior to randomization
• Must have progressed on, or is intolerant to, previous T-DXd tx
• Must have received 2-4 lines of HER2-directed tx in MBC
  • Prior HER2-targeted (neo)adj tx with relapse within 6 months is a line of tx
  • Post-T-DXd therapy allowed (for ex: tucatinib-based regimen and/or T-DM1)
  • Prior participating in a zanidatamab clinical study is excluded
• Measurable disease per RECIST v1.1
• Treated or clinically inactive CNS metastases are eligible
• Washout periods for prior anticancer tx before randomization:
  • Monoclonal antibodies including ADCs: ≤ 3 weeks
  • Small molecule targeted tx: ≤ 2 weeks or 5 half-lives, whichever is shorter
  • No washout needed for ET or gonadotropin-releasing hormone agonists

A phase III, open-label, randomised study of Datopotamab Deruxtecan (Dato-DXd) with or without Durvalumab compared with investigator’s choice of chemotherapy (paclitaxel, nab-paclitaxel or gemcitabine + carboplatin) in combination with pembrolizumab in patients with PD-L1 positive locally recurrent inoperable or metastatic Triple-negative Breast Cancer (TROPION-Breast05)

MOA:

Dato-DXd is a TROP2 targeted ADC with a topoisomerase I inhibitor payload

Durvalumab is a PD-L1
inhibitor

Key Eligibility Criteria:

• Locally recurrent inoperable or metastatic TNBC
  • ER, PgRIHC < 1%, HER2 IHC 0, 1+ or 2+ with ISH
  • de novo mTNBC eligible if anthracycline is contraindicated
• PD-L1+ by 22C3 assay, CPS ≥10 by IHC (centrally confirmed)
• No prior chemo or targeted systemic tx in metastatic setting
  • PD must be ≥6 months after completion of tx with curative intent
  • Adjuvant radiation therapy not considered tx with curative intent for DFI
• (Neo)adjuvant anthracycline required unless contraindicated
• Prior (neo)adjuvant tx with PD-(L)1 inhibitor allowed
• Germline BRCAm with no other tx option are eligible
• Metastatic tumor sample must be provided. Archival tissue from early-stage
  TNBC can be considered if collected ≤3 years prior to consent
• Measurable disease per RECIST v1.1. Bone-only disease is not eligible
• Prior tx containing topo I inhibitor-targeted tx (incl ADC) and TROP2-targeted tx
  are excluded
• Neoplastic spinal cord compression or active brain metastases are excluded

Phase 2 Single Arm Trial with a Safety Lead-in of Tucatinib in Combination with Doxil for the Treatment of HER2+ Metastatic Breast Cancer (BRE 381)

MOA: Tucatinib is an oral tyrosine kinase inhibitor selective for HER2

Doxil is an anthracycline topoisomerase II inhibitor

Key Eligibility Criteria:

• Women, men with HER2+ (IHC3+ or FISH+ by local testing) MBC
• Prior tx with at least 1L anti-HER2 tx in metastatic setting or
  relapsed w/in 6 mo of completion of adjuvant anti-HER2 tx
  • Prior tx with tucatinib in metastatic setting allowed
  • Prior tx with anthracycline (any setting) excluded
• Measurable disease per RECIST v1.1
  • CNS Inclusion – patients must have one of the following:
    • No evidence of brain metastases
    • Untreated brain metastases not needing immediate local
      therapy. Lesions >2.0 cm require approval from Medical
      Monitor.
• Previously treated brain metastases that are stable or have
  progressed but do not require immediate re-treatment
  • Time since WBRT ≥14 days prior to first dose of tx
  • Time since SRS ≥7 days prior to first dose of tx
  • Time since surgical resection ≥28 days

CAMBRIA-2: A Phase III, Open-Label, Randomised Study to Assess the Efficacy and Safety of Camizestrant (AZD9833, a Next Generation, Oral Selective Estrogen Receptor Degrader) vs Standard Endocrine Therapy (Aromatase Inhibitor or Tamoxifen) as Adjuvant Treatment for Patients With ER+/HER2- Early Breast Cancer and an Intermediate-high or High risk of Recurrence Who Have Completed Definitive Locoregional Treatment and Have No Evidence of Disease (D8535C00001)

MOA: Camizestrant is an oral selective estrogen receptor degrader (SERD)

Key Eligibility Criteria:

• ER+ (>10%)/HER2-negative early-stage invasive BC with no evidence of metastatic disease
• Pts must meet criteria for high or intermediate-high risk of recurrence
• Completed breast surgery +/- radiotherapy, +/- (neo)adj chemo
• Pts must be randomized w/in 12 weeks after RT or last dose of chemotherapy. Pts may have received up to 12 weeks of ET in (neo)adjuvant setting prior to randomization
• Pts may have received abemaciclib up to 12 weeks prior to randomization
• Pts with pCR or RCB-0 after neoadjuvant chemo are excluded
• Pts must be randomized within 12 months of breast surgery

A Randomized, Multicenter, Placebo-controlled, Phase 3 study to Evaluate the Efficacy and Safety of HER2/neu Peptide GLSI-100 (GP2 + GM-CSF) in HER2/neu Positive Subjects with Residual Disease or High-Risk PCR after both Neoadjuvant and Postoperative Trastuzumab-based Therapy (FLAMINGO-01)

MOA: GLSI-100 is the intradermal administration of GP2, a HER2/neu protein, and GM-CSF. GLSI-100 induces a CD8+ T cell response targeted to HER2- positive cells

Key Eligibility Criteria:

• Histologically confirmed HER2+ primary BC
• Stage I, II, or III at presentation with residual disease at surgery or Stage III at
  presentation with pCR at surgery
• Stage IV disease is excluded
• All HLA types are eligible. HLA screening can occur as early as surgery (blood
  test).
• Completion of primary SOC BC therapy
  • At least 6 cycles of neoadjuvant chemotherapy
    • MUST include at least 3 cycles of taxane-based chemo over 9 weeks
    • May include anthracycline-based chemo
    • At least 3 cycles of trastuzumab (or approved biosimilar) over 9 weeks
• Surgery
• Adjuvant tx with at least 90% of planned post-surgical trastuzumab-based (or
  approved biosimilar) tx
  • For residual disease at surgery, T-DM1 must be attempted as 1st tx
  • For pCR at surgery, adjuvant trastuzumab-based tx must be completed (at
    least 16 cycles total over one year)
• Pts may continue hormone-based therapy but must not be receiving
  chemotherapy. Concurrent neratinib is prohibited.

MammaPrint, BluePrint, and Full-genome Data Linked with Clinical Data to Evaluate New Gene Expression Profiles: An Adaptable Registry (FLEX Registry)

Brief Summary:  The FLEX Registry will be implemented to operate as a large-scale, population based, prospective registry. All patients with stage I to III breast cancer who receive MammaPrint® and BluePrint testing on a primary breast tumor are eligible for entry into the FLEX Registry, which is intended to enable additional study arms at low incremental effort and cost. FLEX Registry will utilize an adaptive design, where additional targeted substudies and arms can be added after the initial study is opened.

Key Eligibility Criteria:

• Stage I, II, or III patients who receive MammaPrint, with or without BluePrint testing (male or female)
• Informed consent form signed on the same day or before enrollment
• New primary lesion
• Tumor sample shipped to Agendia with ≤ 30% tumor cells or that fails QA or QC criteria excluded
• Metastatic disease excluded
• Recurrent disease excluded
• Stage 0 disease excluded