Inhibition of AKT in combination with antibodies targeting the protein HER2 in patients with advanced or metastatic breast cancer and with a mutation in the gene PIK3CA

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Solti Group

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Feb 2020 → 17 Jun 2025

Decision date (initial)

2024-06-25

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

F. Hoffmann-La Roche Ltd

External identifiers

EU CT number

2023-508826-92-00

EudraCT number

2019-001526-94

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To define the Recommended Phase 2 Dose (RP2D) of ipatasertib when used in combination with HP (+/- ET)

Secondary objectives 2

1. To evaluate the safety and tolerability of the combination of ipatasertib with HP (+/- endocrine therapy [ET]).
2. To assess the preliminary anti-tumor activity of the combination of ipatasertib with HP (+/- ET) as maintenance therapy after first line treatment for HER2-positive metastatic BC with a taxane or vinorelbine plus HP.

Conditions and MedDRA coding

Patients with PIK3CA-mutant, HER2-positive locally advanced or metastatic breast cancer, candidates to receive maintenance therapy with trastuzumab plus pertuzumab (HP) after first line treatment for metastatic disease with a taxane or vinorelbine plus HP.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 19

1. Written and signed informed consent for all study procedures according to local regulatory requirements prior to beginning of specific protocol procedures.
2. Female (pre- or postmenopausal) or male patients.
3. Age ≥ 18 years.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
5. Confirmed HER2-positive invasive breast cancer by central determination defined by the current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice guidelines.
6. Known hormone receptor status, as assessed locally, defined by the current ASCO/CAP clinical practice guidelines. ER/PR positivity is defined as the presence of ≥ 1% of tumor cells with nuclear staining.
7. Histologically confirmed, locally advanced or metastatic adenocarcinoma of the breast. Patients with unresectable locally advanced disease must have recurrent or progressive disease, which must not be amenable to resection with curative intent at the moment of taxane or vinorelbine + HP initiation. Patients with available standard curative options are not eligible. b. For patients with bilateral breast cancer, HER2-positivity must be demonstrated in both locations or in a metastatic biopsy.
8. Patient must be a candidate to receive maintenance HP after first line treatment for metastatic disease with at least 4 cycles of taxane or vinorelbine plus HP.
9. Prior taxane or vinorelbine must have been discontinued for a reason other than progressive disease.
10. Patients may or may not have received neo/adjuvant therapy but must have a disease-free interval from completion of anti-HER2 therapy to metastatic diagnosis ≥6 months.
11. PIK3CA mutation identified and confirmed in tumor tissue or plasma ctDNA by central determination. If prior approval has been granted by the Sponsor, centrally confirmed PIK3CA mutation result from a current or previous study identified by the sponsor can be used to determine eligibility for this study.
12. Start of treatment with ipatasertib plus HP no later than 9 weeks after last dose of taxane or vinorelbine plus HP (i.e., maximum of 2 HP administrations with no taxane or vinorelbine).
13. Willingness and ability to provide archived formalin fixed paraffin embedded (FFPE) tissue block.
14. No baseline diarrhea or diarrhea grade ≤1 within the last 28 days.
15. Adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of Cycle 1, defined by the following: a. Neutrophils (ANC ≥1500/μL) b. Hemoglobin ≥9 g/dL (with no need for transfusions in the last 14 days). c. Platelet count ≥75,000/μL d. Serum albumin ≥3 g/dL e. Total bilirubin ≤1.5x the upper limit of normal (ULN), with the exception: patients with known Gilbert syndrome who have serum bilirubin ≤3x ULN. f. AST and ALT ≤2.5x ULN, with the following exception: patients with documented liver or bone metastases who may have AST and ALT ≤5x ULN. g. ALP ≤2x ULN, with the following exceptions: - Patients with known liver involvement who may have ALP ≤5x ULN. - Patients with known bone involvement who may have ALP ≤7x ULN. h.PTT (or aPTT) and INR ≤1.5x ULN (except for patients receiving anticoagulation therapy). - Patients receiving heparin treatment should have a PTT (or aPTT) between 1.5 and 2.5x ULN. - Patients receiving coumarin derivatives should have an INR between 2.0 and 3.0 assessed in two consecutive measurements 1 to 4 days apart. i. Serum creatinine <1.5x ULN or creatinine clearance ≥50 mL/min based on Cockcroft−Gault glomerular filtration rate estimation: (140 − age) x (weight in Kg) x 0.85 (if female) 72 x (serum creatinine in mg/dL) j. Fasting total serum glucose ≤150mg/dL and glycosylated hemoglobin (HbA1C) ≤7.5%
16. Life expectancy of at least 6 months.
17. Baseline left ventricular ejection fraction (LVEF) ≥50% measured by echocardiography (ECHO) or Multiple Gate Acquisition (MUGA) scan.
18. Negative β-HCG pregnancy test (serum) for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after the menopause. All subjects who are biologically capable of having children must agree and commit to the use of a reliable method of birth control from 2 weeks before administration of the first dose of investigational product until 28 days after the last dose of investigational product
19. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial.

Exclusion criteria 24

1. Last dose of taxane or vinorelbine plus HP given more than 9 weeks prior to C1D1.
2. Prior malignancy within 3 years prior to randomization, except curatively treated non-melanoma skin, carcinoma in situ of the cervix or Stage I uterine cancer.
3. Brain metastases that have not been treated previously, are progressive, or require any type of therapy (e.g., radiation, surgery, or steroids) to control symptoms within 30 days prior to the first study treatment dose.
4. Radiotherapy for metastatic sites of disease outside of the brain performed within 14 days prior to study enrollment and/or radiation of >30% of marrow-bearing bone
5. Symptomatic hypercalcemia requiring use of bisphosphonate or RANKL inhibitors therapy within 21 days prior to the first study treatment. Patients who receive bisphosphonate therapy specifically to prevent skeletal events are eligible if they have been initiated prior to the treatment to study.
6. Cardiopulmonary dysfunction as defined by: a. Inadequately controlled angina or serious cardiac arrhythmia not controlled by adequate medication. b. Inadequate LVEF at baseline, as defined as LVEF <50% by either ECHO or MUGA scan. c. History of symptomatic congestive heart failure (CHF): Grade ≥3 per NCI CTCAE version 4.03 or Class ≥II New York Health Association (NYHA) criteria. d. History of a decrease in LVEF to <40% or symptomatic CHF with prior trastuzumab or HP treatment. e. History of myocardial infarction within 6 months prior to randomization. f. Current dyspnea at rest due to complications of advanced malignancy, or other disease requiring continuous oxygen therapy.
7. Congenital long QT syndrome or screening QT interval corrected using Fridericia's formula (QTcF) > 480 milliseconds.
8. Concurrent, serious, uncontrolled infections or current known infection with HIV (testing is not mandatory).
9. History of intolerance, including Grade 3-4 infusion reaction or hypersensitivity, to trastuzumab or pertuzumab.
10. Known hypersensitivity to any of the study drugs, including excipients.
11. Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (e.g., positive for hepatitis B surface antigen [HBsAg] or hepatitis C virus [HCV] antibody at screening), current drug or alcohol abuse, or cirrhosis. - Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [HBcAg] antibody test) are eligible. -Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
12. History of Type I or Type II diabetes mellitus requiring insulin. Patients who are on stable dose of oral diabetes medication > 2 weeks prior to initiation of study treatment are eligible for enrollment.
13. Grade ≥2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia.
14. History of or active inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis) or active bowel inflammation (e.g., diverticulitis).
15. Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis, cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunistic infections (Pneumocystis pneumonia or Cytomegalovirus pneumonia).
16. Need for chronic corticosteroid therapy of >10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids for a chronic disease.
17. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters (e.g., PleurX®) are allowed.
18. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 2 weeks or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug.
19. Prior treatment with an AKT inhibitor. Prior PI3K or mTOR inhibitors are allowed.
20. Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary or metabolic disease; wound healing disorders; ulcers; bone fractures).
21. Unresolved, clinically significant toxicity from prior therapy, except for alopecia and Grade 1 peripheral neuropathy.
22. Major surgical procedure or significant traumatic injury within 28 days prior to enrollment
23. Assessment by the investigator to be unable or unwilling to comply with the requirements of the protocol.
24. History of significant comorbidities that, in the judgment of the investigator, may interfere with the conduction of the study, the evaluation of response, or with informed consent

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Determination of the Maximum Tolerated Dose (MDT), defined as the highest dose level at which no more than 1 of 6 subjects experiences a DLT during the DLT assessment window (28 days), and recommended phase 2 dose (RP2D), as assessed by the Steering Committee.

Secondary endpoints 7

1. For A): - Overall incidence and severity of adverse events (AEs) and severe adverse events (SAEs) as per NCI CTCAE v4.03 of the combination of ipatasertib plus HP (+/- ET), with a special emphasis on the onset and severity of diarrhea.
2. For B): - Objective Response Rate (ORR), defined as the proportion of patients who have a complete response (CR) or partial response (PR), as determined by the investigator through use of RECIST v1.1.This endpoint will only be determined in patients without CR after taxane or vinorelbine + HP induction therapy
3. Duration of Response (DoR), defined as the time from the first occurrence of a documented Objective Response (OR) to disease progression, according to RECIST v1.1, or death from any cause, whichever occurs first.This endpoint will only be determined in patients without CR after taxane or vinorelbine + HP induction therapy.
4. Clinical Benefit Rate (CBR) defined as the percentage of patients achieving confirmed CR, PR or stable disease (SD) for at least 24 weeks after the beginning of the study treatment by RECIST v1.1.
5. Progression-free survival (PFS), defined as the time from the commencement of study treatment (Day 1) to the occurrence of PD, as determined by the investigator via RECIST v1.1, or death from any cause, whichever occurs first.
6. Safety: incidence of Dose Limiting Toxicity (DLT) in the evaluation period.
7. Tolerability: dose interruptions, reductions, and dose intensity

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Solti Group

Sponsor organisation

Solti Group

Address

Calle Balmes 89 Planta 1 Puerta 2

City

Barcelona

Postcode

08008

Country

Spain

Scientific contact point

Organisation

Solti Group

Contact name

SOLTI-Start-Up Group

Public contact point

Organisation

Solti Group

Contact name

SOLTI-Start-Up Group

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications