| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ER+ Locally Advanced or Metastatic Breast Cancer and Other Select Non-Breast Cancers |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To identify the RP2D of LY3484356 administered as monotherapy and in combination with other anticancer therapies in patients with locally advanced or metastatic ER+ breast cancer or ER+ recurrent, persistent, or metastatic EEC. |
|
| E.2.2 | Secondary objectives of the trial |
- To assess the safety and tolerability of LY3484356 administered as monotherapy and in combination with other anticancer therapies in patients with locally advanced or metastatic ER+ breast cancer or ER+ recurrent, persistent, or metastatic EEC.
- To assess the PK of LY3484356, administered as monotherapy and in combination with other anticancer therapies in patients with locally advanced or metastatic ER+ breast cancer or ER+ recurrent, persistent, or metastatic EEC.
- To document any antitumor activity per RECIST v1.1 observed with LY3484356, when administered as monotherapy and in combination with other anticancer therapies in patients with locally advanced or metastatic ER+ breast cancer or ER+ recurrent, persistent, or metastatic EEC. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
6. Have histological or cytological diagnosis of one of the following:
- Phase 1a and Phase 1b Parts A and B: ER+ and HER2- breast cancer with evidence of locally advanced unresectable or metastatic disease
- Phase 1b Part C: ER+ and HER2+ breast cancer with evidence of locally advanced unresectable or metastatic disease
- Phase 1a and Phase 1b Part D: ER+ recurrent, persistent, or metastatic EEC
- For breast cancer patients, ER and HER2 status assessed from the most recent tissue biopsy taken at the time of presentation with recurrent or metastatic disease.
o To fulfill the requirement for ER+ disease by local testing, ≥1% of tumor cell nuclei must be immunoreactive by immunohistochemistry defined in the relevant American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) Guidelines (Allison et al. 2020).
o To fulfill the requirement of HER2- disease by local testing on primary disease specimen, tumor must be HER2- according to ASCO/CAP guidelines for HER2 testing (Wolff et al. 2018).
o To fulfill the requirement of HER2+ disease, tumor must be HER2+ as defined by in situ hybridization or FISH or IHC methodology in the relevant ASCO/CAP HER2 guidelines (Wolff et al. 2018).
- For EEC patients, ER+ status determined by local testing.
34. Phase 1a and Phase 1b Parts A and B: breast cancer patients must have either:
a. Untreated de novo metastatic disease or
b. Demonstrated sensitivity to prior ET by 1 of the following:
i. Documented clinical benefit (complete response [CR], PR, stable disease [SD] ≥24 weeks) to at least 1 prior ET in the metastatic setting or
ii. At least 24 months of adjuvant ET prior to recurrence, with the exception of patients who discontinued prior adjuvant ET earlier for reasons other than progressive disease.
35. Prior therapies received in the metastatic setting:
- Phase 1a: breast cancer patients may have had up to 3 prior regimens (no restrictions on types of prior therapies)
- Phase 1b Part A: patients may have had up to 1 prior regimen of any kind for advanced/mBC but must not have received a prior CDK4/6 inhibitor.
- Phase 1b Part B: patients may have had up to 2 prior regimens, no more than 1 of which may be ET and must have received a prior CDK4/6 inhibitor or be deemed inappropriate for or refused such therapy.
o Cohort E4: patients must not have had prior everolimus
o Cohort E5: patients must have a known PIK3Cα mutation as determined by local testing and must not have had prior alpelisib
- Phase 1b Part C: patients must have had at least 2 HER2-directed therapies for advanced disease and prior trastuzumab, pertuzumab, and TDM-1 required in any setting. Patients must have left ventricular ejection fraction (LVEF) of 50% or higher at baseline (determined by echocardiography or multigated acquisition scanning). Patients must not have received prior CDK4/6 inhibitor therapy or fulvestrant.
- Phase 1a EEC patients and Phase 1b Part D: patients must have progressed after platinum-containing chemotherapy, be deemed inappropriate for or declined platinum-containing chemotherapy, and must not have had prior fulvestrant or AI therapy.
7. Measurability of Lesions:
a) Breast cancer patients must have one of the following as defined by RECIST v1.1
(Eisenhauer et al. 2009):
- Measurable disease
- Nonmeasurable bone-only disease. Nonmeasurable bone-only disease may include any of the following:
i. blastic bone lesions
ii. lytic bone lesions without a measurable soft tissue component
iii. mixed lytic-blastic bone lesions without a measurable soft tissue component.
b) EEC patients must have at least 1 measurable lesion assessable using standard techniques by RECIST v1.1 (Eisenhauer et al. 2009).
8. Patients must be willing to provide an adequate archival tissue sample (primary or metastatic disease). Preferably, the most recently obtained nonbone biopsy should be provided. Patients without archival material may be enrolled after consultation with the Lilly CRP/CRS.
9.Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group scale (Oken et al. 1982).
10. Have adequate organ function, |
|
| E.4 | Principal exclusion criteria |
1. Have symptomatic central nervous system (CNS) metastasis and/or carcinomatous meningitis.
2. Have a serious concomitant systemic disorder
3. Have pre-existing nausea, vomiting or diarrhea > grade 1 per CTCAE5.0.
4. Have visceral crisis.
5. Have inflammatory breast cancer .
6. Have an serious cardiac condition
7. Diagnosed and/or treated malignancy within 3 years prior to enrolment.
8.Have had major surgery within 28 days prior to randomization to allow for post-operative healing of the surgical wound and site(s).
9. Patients should refrain from consuming grapefruit, grapefruit juice, and grapefruit-containing products while on study due to the effect on CYP3A4 – |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
DLTs
DLT-equivalent toxicities in dose expansion Parts A through D |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| To identify the RP2D of LY3484356 administered as monotherapy and in combination with other anticancer therapies in patients with locally advanced or metastatic ER+ breast cancer and ER+ recurrent, persistent, or metastatic EEC |
|
| E.5.2 | Secondary end point(s) |
1. Safety endpoints, including but not limited to the following:
o TEAEs, SAEs, clinical laboratory tests, vital signs, and physical examinations
2. Plasma concentration of LY3484356 alone and when administered in combination with other therapeutic therapies
3.
- ORR
- DoR
- DCR
- CBR
- PFS |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. To assess the safety and tolerability of LY3484356 administered as monotherapy and in combination with other anticancer therapies in patients with locally advanced or metastatic ER+ breast cancer and ER+ recurrent, persistent, or metastatic EEC
2. To assess the PK of LY3484356, administered as monotherapy and in combination with other anticancer therapies in patients with locally advanced or metastatic ER+ breast cancer and ER+ recurrent, persistent, or metastatic EEC
3. To document any antitumor activity per RECIST v1.1 observed with LY3484356, when administered as monotherapy and in combination with other anticancer therapies in patients with locally advanced or metastatic ER+ breast cancer and ER+ recurrent, persistent, or metastatic EEC |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| First Human dose, multicenter, open-label - dose escalation followed by a randomized dose-expansion |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 9 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 14 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| France |
| Japan |
| Korea, Democratic People's Republic of |
| Spain |
| Taiwan |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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