A study to evaluate the safety, tolerability, processing by the body, and antitumor activity of inavolisib and paclitaxel

ISRCTN	ISRCTN45319897
DOI	https://doi.org/10.1186/ISRCTN45319897
EudraCT/CTIS number	2020-005057-24
Secondary identifying numbers	CO42800

Submission date: 18/05/2021
Registration date: 07/07/2021
Last edited: 19/09/2024

Recruitment status: No longer recruiting
Overall study status: Ongoing
Condition category: Cancer

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Background and study aims
This study will evaluate the safety (side effects), how the body processes the treatment (pharmacokinetics), what the treatment does to the body (pharmacodynamic effects), and preliminary anti-cancer activity of the drug inavolisib given in combination with the drug paclitaxel in patients with locally advanced or metastatic solid tumors, and of inavolisib given in combination with paclitaxel, in patients with locally advanced or metastatic PIK3CA-mutated (altered gene), HER2-positive breast cancer. Locally advanced cancer is cancer that has spread only to nearby tissues or lymph nodes, while metastatic cancer is cancer that has spread to other parts of the body.

Who can participate?
Part 1, Arm A: Patients aged 18 years and over with locally advanced or metastatic solid tumors
Part 2, Arm A: Patients aged 18 years and over with locally advanced or metastatic PIK3CA-mutated cancer

What does the study involve?
Up to 104 patients at various hospital locations around the world will take part in this study. The study is divided into two parts. Part 1, Arm A is the dose-escalation (dose-finding) part of the study. Part 2 consists of Arm A which will be treatment expansions after dose-finding is complete.
Part 1, Arm A: inavolisib will be tested at different doses and schedules in combination with paclitaxel in up to 24 patients with locally advanced or metastatic cancer
Part 2, Arm A: a dose and schedule of inavolisib determined to be safe in Part 1, Arm A will be tested in combination with paclitaxel, in about 80 patients with locally advanced or metastatic PIK3CA mutated (altered gene) cancer.
Patients will have the following assessments and measurements:
1. Vital signs - temperature, pulse rate, blood pressure, breathing rate and oxygen level
2. Complete or limited physical exam
3. Assessment of performance status
4. Electrocardiogram (ECG): measuring the electrical activity of the heart
5. Urine sample for standard laboratory tests
6. Blood samples for standard laboratory tests and to measure study treatment levels (pharmacokinetics)
7. Tumor tissue samples (biopsies)
8. Tumor assessments: scans of the internal organs and bones that may include a computed tomography (CT) scan, a magnetic resonance imaging (MRI) scan, or a bone scan
9. Eye examination

What are the possible benefits and risks of participating?
The patient's cancer and health may or may not improve in this study, but the information collected may help other people who have a similar medical condition in the future.
High blood sugar, oral inflammation/ulcers, rash, and diarrhea/colitis (colon inflammation) are identified risks for inavolisib. Pneumonitis (lung inflammation), immunosuppressant effects, reproductive effects, eye toxicities, and embryo-fetal toxicities are potential risks for inavolisib. Results to date have shown good tolerability, with no additional safety concerns beyond those associated with expected toxicities. Paclitaxel is known to cause decrease in the activity of the gelatinous tissue that fills the cavities, or the centers of bones (bone marrow suppression), hypersensitivity reactions, joint or muscle pain, oral inflammation/ulcers, nerve damage, alopecia (hair loss), injection site reactions, and vascular (blood vessel) disorders. Given that these risks may require either dose interruptions and/or dose reductions or may have the potential to cause life-threatening conditions, close monitoring and a robust risk-mitigation strategy will be implemented during this study. Since immunosuppressant effects are a potential risk for inavolisib and bone marrow suppression is very commonly associated with the use of paclitaxel, a possible consequence of immunosuppression may be an increased susceptibility to acute infections including COVID-19. At this time, there is insufficient evidence for a causal association between inavolisib and an increased risk of severe outcomes from COVID-19.
Pneumonitis (lung inflammation) is a potential risk for inavolisib and a few cases of Grade 1, 2 pneumonitis have been observed after treatment with inavolisib. There may be a potential overlap in clinical and radiological features for inavolisib-induced pneumonitis and COVID-19-related interstitial pneumonia. Available non-clinical and clinical data for inavolisib support the proposed evaluation of inavolisib in combination with paclitaxel in solid tumors in this study. Considering the known safety profiles of inavolisib and paclitaxel and the safety risk mitigation measures incorporated in this study, it is anticipated that the combination treatments in this study will have a manageable safety profile and an acceptable benefit-risk assessment for the conduct of the study.

Where is the study run from?
Genentech, Inc (USA)

When is the study starting and how long is it expected to run for?
July 2020 to October 2025

Who is funding the study?
Genentech, Inc (USA)

Who is the main contact?
global-roche-genentech-trials@gene.com

Study website

Contact information

Mr Clinical Trials
Public

1 DNA Way
South San Francisco
94080
United States of America

Phone	+1 (0)888 662 6728
Email	global-roche-genentech-trials@gene.com

Study information

Study design	Open-label multicenter phase Ib study
Primary study design	Interventional
Secondary study design	Non randomised study
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	No participant information sheet available
Scientific title	A Phase Ib, open-label, dose-escalation and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of inavolisib in combination with paclitaxel in patients with locally advanced or metastatic solid tumors
Study objectives	Current study hypothesis as of 20/07/2022: The aim is to evaluate the safety, pharmacokinetics, pharmacodynamic (PD) effects, and preliminary anti-tumor activity of inavolisib administered in combination with paclitaxel in patients with locally advanced or metastatic solid tumors and locally advanced or metastatic PIK3CA-mutated, HER2-positive breast cancer. Previous study hypothesis: The aim is to evaluate the safety, pharmacokinetics, pharmacodynamic (PD) effects, and preliminary anti-tumor activity of inavolisib administered in combination with paclitaxel in patients with locally advanced or metastatic solid tumors, and of inavolisib administered in combination with paclitaxel, trastuzumab and pertuzumab in patients with locally advanced or metastatic PIK3CA-mutated, HER2-positive breast cancer.
Ethics approval(s)	1. Approved 29/04/2021, Narodowy Instytut Onkologii Im. M. Sklodowskiej-Curie; Oddzial Badan Wczesnych Faz, Ethics Board (Komisja Bioetyczna przy Narodowym Instytucie Onkologii im. M.Sklodowskiej-Curie ul. W.K. Roentgena 5, 02-781 Warszawa, Poland; +48 (0)22 546 33 60, email: not applicable), ref: not applicable 2. Approved 23/04/2021, START Madrid. Centro Integral Oncologico Clara Campal; CIOCC Ethics Board (Comité de Ética de Investigación Clínica HM Hospitales Avda. Montepríncipe, 25, 28660, Boadilla del Monte, Madrid, Spain; +34 (0)91 708 99 00 Ext 2588; secretariaceic@hmhospitales.com), ref: not applicable
Health condition(s) or problem(s) studied	Solid tumors, Breast cancer
Intervention	Current interventions as of 20/07/2022: The study is an open-label design and the treatments include: Inavolisib - 6 mg/9 mg taken orally every day and potentially on an intermittent weekly schedule of 6/1 or 5/2, until disease progression or unacceptable toxicity. Paclitaxel - Intravenous infusion 80 mg/m² dose weekly, until disease progression or unacceptable toxicity. Up to 104 patients at various hospital locations around the world will take part in this study. The study is divided into two parts. Part 1, Arm A is the dose-escalation (dose-finding) part of the study. Part 2, Arm A which will be treatment expansion after dose-finding is complete. Participants will be allocated to the different treatments based on inclusion and exclusion criteria for Part 1 and Part 2: Part 1, Arm A: inavolisib will be tested at different doses and schedules in combination with paclitaxel in up to 24 patients with locally advanced or metastatic cancer Part 2, Arm A: a dose and schedule of inavolisib determined to be safe in Part 1, Arm A will be tested in combination with paclitaxel, in approximately 80 patients with locally advanced or metastatic PIK3CA mutated (altered gene) cancer. Participants will be enrolled into four cohorts depending on the tumor type: PIK3CAmutated Head and neck squamous cell carcinoma (HNSCC) (Cohort 1), ovarian cancer (Cohort 2), triple-negative breast cancer (TNBC) (Cohort 3), and endocrine-resistant/refractory positive, HER2 negative breast cancer (Cohort 4). Patients will have the following assessments and measurements: 1. Vital signs - temperature, pulse rate, blood pressure, breathing rate and oxygen level 2. Complete or limited physical exam 3. Assessment of performance status (Eastern Cooperative Oncology Group daily functioning) 4. Electrocardiogram (ECG) 5. Urine sample for standard laboratory tests 6. Blood samples for standard laboratory tests and to measure pharmacokinetics 7. Tumor tissue biopsies 8. Tumor assessments: scans of internal organs and bones that may include: 8.1. Computed tomography (CT) scan 8.2. Magnetic resonance imaging (MRI) scan 8.3. Bone scan 9. Eye examination Previous interventions: The study is an open-label design and the treatments include: Inavolisib - 6 mg/9 mg taken orally every day and potentially on an intermittent weekly schedule of 6/1 or 5/2, until disease progression or unacceptable toxicity. Paclitaxel - Intravenous infusion 80 mg/m² dose weekly, until disease progression or unacceptable toxicity. Trastuzumab - Intravenous infusion every 3 weeks. Loading dose of 8 mg/kg for Cycle 1 and a dose of 6 mg/kg for subsequent cycles, until disease progression or unacceptable toxicity. Pertuzumab - Intravenous infusion every 3 weeks. Loading dose of 840 mg for the first cycle and a dose of 420 mg for subsequent cycles, until disease progression or unacceptable toxicity. Up to 120 patients at various hospital locations around the world will take part in this study. The study is divided into two parts. Part 1, Arm A is the dose-escalation (dose-finding) part of the study. Part 2 consists of Arm A and Arm B, which will be treatment expansions after dose-finding is complete. Participants will be allocated to the different treatments based on inclusion and exclusion criteria for Part 1 and Part 2: Part 1, Arm A: inavolisib will be tested at different doses and schedules in combination with paclitaxel in up to 24 patients with locally advanced or metastatic cancer Part 2, Arm A: a dose and schedule of inavolisib determined to be safe in Part 1, Arm A will be tested in combination with paclitaxel, in approximately 76 patients with locally advanced or metastatic PIK3CA mutated (altered gene) cancer. Part 2, Arm B: a dose and schedule of inavolisib determined to be safe in Part 1, Arm A will be tested in combination with paclitaxel, trastuzumab and pertuzumab in approximately 20 patients with locally advanced or metastatic PIK3CA-mutated (altered gene) HER2 positive breast cancer Patients will have the following assessments and measurements: 1. Vital signs - temperature, pulse rate, blood pressure, breathing rate and oxygen level 2. Complete or limited physical exam 3. Assessment of performance status (Eastern Cooperative Oncology Group daily functioning) 4. Electrocardiogram (ECG) 5. Urine sample for standard laboratory tests 6. Blood samples for standard laboratory tests and to measure pharmacokinetics 7. Tumor tissue biopsies 8. Tumor assessments: scans of internal organs and bones that may include: 8.1. Computed tomography (CT) scan 8.2. Magnetic resonance imaging (MRI) scan 8.3. Bone scan 9. Eye examination
Intervention type	Drug
Pharmaceutical study type(s)	Not Applicable
Phase	Phase I
Drug / device / biological / vaccine name(s)	Inavolisib, paclitaxel
Primary outcome measure	Safety Objectives: 1. Incidence and nature of dose-limiting toxicities (Part 1 only) measured using adverse events (graded by NCI CTCAE v5.0) recorded within the first 28 days (cycle 1) of study treatment 2. Incidence, type, and severity of adverse events including serious adverse events graded by NCI CTCAE v5.0 recorded throughout the study 3. Targeted vital signs measured using standard techniques assessed by site staff at baseline and weekly/monthly during study treatment 4. Targeted clinical laboratory test results measured using standard hospital laboratory analyses at baseline and taken every week/cycle, including ECGs, recorded by taken by site staff at baseline and every cycle during study treatment
Secondary outcome measures	Current secondary outcome measures as of 20/07/2022: Pharmacokinetic Objective (Secondary Objective): Plasma concentration of inavolisib administered in combination with paclitaxel (Arm A) measured by a bioanalytical laboratory at Cycles 1-3. The following PK parameters will be determined as appropriate: 1. Area under the concentration-time curve (AUC) 2. Maximum plasma concentration (Cmax) 3. Minimum plasma concentration (Cmin) 4. Additional plasma PK parameters as warranted Activity/Efficacy Objectives (Secondary Objectives): Preliminary assessment of the anti-tumor activity of: 1. Inavolisib administered in combination with paclitaxel in patients with locally advanced or metastatic PIK3CA-mutated solid tumors (Part 2 Arm A) The corresponding endpoints are as follows: 1. Objective response rate (ORR) defined as a complete recovery (CR) or partial recovery (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator through use of RECIST v1.1 every 8() weeks during the study treatment 2. Best overall response (BOR) defined as the proportion of patients with a CR or PR, as determined by the investigator through use of RECIST v1.1 every 8() weeks during study treatment 3. Duration of response (DOR) defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through the use of RECIST v1.1, or death, whichever occurs first, every 8() weeks during study treatment 4. Clinical benefit rate (CBR) defined as the percentage of patients achieving confirmed RECIST v1.1 defined CR, PR, or stable disease (SD; non-complete response/non-progressive disease for patients with non-measurable disease at baseline) ≥24 weeks, as determined by the investigator through use of RECIST v1.1 every 8() weeks during study treatment 5. Progression-free survival (PFS) defined as the time from the first study treatment (Day 1) to the first occurrence of disease progression, as determined by the investigator through the use of RECIST v1.1 every 8() weeks during study treatment, or death, whichever occurs first Previous secondary outcome measures: Pharmacokinetic Objective (Secondary Objective): Plasma concentration of inavolisib administered in combination with paclitaxel (Arm A), or with paclitaxel, trastuzumab, and pertuzumab (Arm B) measured by a bioanalytical laboratory at Cycles 1-3. The following PK parameters will be determined as appropriate: 1. Area under the concentration-time curve (AUC) 2. Maximum plasma concentration (Cmax) 3. Minimum plasma concentration (Cmin) 4. Additional plasma PK parameters as warranted Activity/Efficacy Objectives (Secondary Objectives): Preliminary assessment of the anti-tumor activity of: 1. Inavolisib administered in combination with paclitaxel in patients with locally advanced or metastatic PIK3CA-mutated solid tumors (Part 2 Arm A) 2. Inavolisib administered in combination with paclitaxel, trastuzumab and pertuzumab in patients with locally advanced or metastatic PIK3CA mutated, HER2-positive breast cancer (#Part 2 Arm B) The corresponding endpoints are as follows: 1. Objective response rate (ORR) defined as a complete recovery (CR) or partial recovery (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator through the use of RECIST v1.1 every 8() or 9(#) weeks during study treatment 2. Best overall response (BOR) defined as the proportion of patients with a CR or PR, as determined by the investigator through the use of RECIST v1.1 every 8() or 9(#) weeks during study treatment 3. Duration of response (DOR) defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through use of RECIST v1.1, or death, whichever occurs first, every 8() or 9(#) weeks during study treatment 4. Clinical benefit rate (CBR) defined as the percentage of patients achieving confirmed RECIST v1.1 defined CR, PR, or stable disease (SD; non-complete response/non-progressive disease for patients with non-measurable disease at baseline) ≥24 weeks, as determined by the investigator through use of RECIST v1.1 every 8() or 9(#) weeks during study treatment 5. Progression-free survival (PFS) defined as the time from the first study treatment (Day 1) to the first occurrence of disease progression, as determined by the investigator through the use of RECIST v1.1 every 8() or 9(#) weeks during study treatment, or death, whichever occurs first
Overall study start date	01/07/2020
Completion date	30/10/2025

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	104
Key inclusion criteria	Current inclusion criteria as of 20/07/2022: 1. Signed Informed Consent Form 2. Aged over 18 years and over 3. Evaluable or measurable disease per RECIST, v1.1 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 5. Life expectancy of >12 weeks 6. Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following: 6.1. Absolute neutrophil count 1500/μl 6.2. Hemoglobin ≥9 g/dl 6.3. Platelet count ≥100,000/l 6.4. Fasting glucose <126 mg/dL or <7 mmol/l and glycosylated hemoglobin (HbA1C) 5.7% or <39 millimoles per mole (mmol/mol) 6.5. Total bilirubin <1.5 upper limit of normal (ULN) 6.6. Serum albumin ≥2.5 g/dl or 25 g/l 6.7. AST and ALT ≤2.5 ULN with the following exception: patients with documented liver metastases may have AST and ALT ≤5.0 ULN. 6.8. Serum creatinine 1.5 ULN or creatinine clearance ≥50 ml/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation 6.9. International normalized ratio (INR) <1.5 x upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) <1.5 x ULN 7. Consent to provide fresh (preferred) or archival tumor tissue specimen. It is preferred that the specimen be from the most recently collected and available tumor tissue, and whenever possible, from a metastatic site of disease. 8. Consent to provide a freshly collected pre-treatment blood sample. 9. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective form of contraceptive method with a failure rate of 1% per year in combination with use of male condom with spermicide (for male partners), unless male sterilization has been confirmed. 10. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive measures, and agreement to refrain from donating sperm. Inclusion Criteria Specific to Patients Enrolling in Part 1, Arm A: Histologically documented, locally advanced, recurrent, or metastatic, incurable solid tumor malignancy that has progressed after available standard systemic therapies; or for whom standard therapy has proven to be ineffective or intolerable; or for whom a clinical trial of an investigational agent is a recognized standard of care. If there are other available SOC therapies, these will be discussed with the patient and documented before informed consent is obtained. Inclusion Criteria Specific to Patients Enrolling in Part 2, Arm A Expansion Cohorts: 1. Histologically documented, locally advanced, recurrent, or metastatic, incurable solid tumor malignancy with a known PIK3CA mutation that has progressed after at least one available standard systemic therapy in the metastatic setting. – Cohort 1 (HNSCC): Histologically or cytologically confirmed recurrent and/or metastatic HNSCC that has been previously treated with systemic therapy in the recurrent and/or metastatic setting, which may include immunotherapy and/or chemotherapy with or without cetuximab. – Cohort 2 (ovarian cancer): Persistent or recurrent epithelial ovarian, fallopian tube, or primary peritoneal tumors that have been previously treated with up to 4 prior regimens in the recurrent and/or metastatic setting, being at least one platinum-based. Patients may have received bevacizumab and/or poly-ADP ribose polymerase (PARP) inhibitors. – Cohort 3 (TNBC): Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic, not amenable to surgical or radiation therapy with curative intent, which has progressed after all available standard therapies, or for which standard therapy has proven to be ineffective or intolerable. – Cohort 4 (endocrine resistant/refractory HR-positive, HER2 negative breast cancer): Histologically or cytologically confirmed adenocarcinoma of the breast that is locally advanced or metastatic and is not amenable to surgical or radiation therapy with curative intent and has progressed after all available endocrine-based standard therapies in the locally advanced/metastatic setting or for which endocrine-based standard therapy has proven to be ineffective or intolerable. 2. Confirmation of biomarker eligibility: valid results from central testing of blood or local testing of blood or tumor tissue documenting PIK3CA-mutated tumor status is required for patients enrolling to Part 2, Arm A, expansion cohorts. Previous inclusion criteria: 1. Signed Informed Consent Form 2. Aged over 18 years and over 3. Evaluable or measurable disease per RECIST, v1.1 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 5. Life expectancy of 12 weeks 6. Adequate hematologic and organ function within 14 days prior to initiation of study treatment, defined by the following: 6.1. Absolute neutrophil count 1500/l 6.2. Hemoglobin 9 g/dl 6.3. Platelet count 100,000/l 6.4. Fasting glucose 126 mg/dL or 7 mmol/l and glycosylated hemoglobin (HbA1C) 5.7% 6.5. Total bilirubin 1.5 upper limit of normal (ULN) 6.6. Serum albumin 2.5 g/dl or 25 g/l 6.7. AST and ALT 2.5 ULN with the following exception: patients with documented liver metastases may have AST and ALT 5.0 ULN. 6.8. Serum creatinine 1.5 ULN or creatinine clearance 50 ml/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation 6.9. International normalized ratio (INR) <1.5 x upper limit of normal (ULN) and activated partial thromboplastin time (aPTT) <1.5 x ULN 7. Consent to provide fresh (preferred) or archival tumor tissue specimen. It is preferred that the specimen be from the most recently collected and available tumor tissue, and whenever possible, from a metastatic site of disease. See the laboratory manual and Section 4.5.7 for specimen requirements. 8. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective form of contraceptive method with a failure rate of 1% per year in combination with use of male condom with spermicide (for male partners), unless male sterilization has been confirmed. 9. For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive measures, and agreement to refrain from donating sperm. Inclusion Criteria Specific to Patients Enrolling in Part 1, Arm A: Histologically documented, locally advanced, recurrent, or metastatic, incurable solid tumor malignancy that has progressed after available standard systemic therapies; or for whom standard therapy has proven to be ineffective or intolerable; or for whom a clinical trial of an investigational agent is a recognized standard of care. If there are other available SOC therapies, these will be discussed with the patient and documented before informed consent is obtained. Inclusion Criteria Specific to Patients Enrolling in Part 2, Arm A Expansion Cohorts: 1. Histologically documented, locally advanced, recurrent, or metastatic, incurable solid tumor malignancy with a known PIK3CA mutation that has progressed after at least one available standard systemic therapy in the metastatic setting. 2. Confirmation of biomarker eligibility: valid results from central testing of blood or local testing of blood or tumor tissue documenting PIK3CA-mutated tumor status is required for patients enrolling to Part 2, Arm A, expansion cohorts. Inclusion Criteria Specific to Patients Enrolling in Part 2, Arm B: 1. Patients with histologically documented locally advanced or metastatic PIK3CA-mutated HER2-positive breast cancer 2. Patients may present with either: de novo metastatic HER2-positive disease for which they have not received any systemic HER2-positive anti-cancer treatment recurrent locally advanced or metastatic disease following prior HER2-positive targeted treatment for early breast cancer, where the diagnosis has been based on the biopsy of the locally recurrent or metastatic disease and the patient has progressed following (neo)adjuvant HER2-positive targeted therapy with a treatment-free interval of 6 months 3. Documented HER2-positive and either HR-positive or HR-negative breast cancer according to ASCO/CAP guidelines based on local assessment HER2-positive 4. Confirmation of biomarker eligibility: valid results from central testing of blood documenting PIK3CA-mutated tumor status is required for patients enrolling to Part 2, Arm B 5. Patients may have received prior paclitaxel and HER2‑directed therapies in the (neo)adjuvant setting, including trastuzumab and pertuzumab, as long as the patients did not discontinue prior paclitaxel, prior trastuzumab, or pertuzumab because of a toxicity assessed as related to one or more of these agents 6. Left ventricular ejection fraction (LVEF) 50%, as determined by either echocardiography (ECHO) (preferred) or multiple gated acquisition (MUGA) scan, at screening 7. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a highly effective form of contraceptive method with a failure rate of 1% per year, and agreement to refrain from donating eggs, during the treatment period and for at least 60 days after the last dose of inavolisib, at least 6 months after the last dose of paclitaxel, at least 7 months after the last dose of pertuzumab and the last dose of trastuzumab.
Key exclusion criteria	1. Metaplastic breast cancer 2. Any history of leptomeningeal disease 3. Type 2 diabetes requiring ongoing systemic treatment at the time of study entry; or any history of Type 1 diabetes 4. Inability or unwillingness to swallow pills 5. Malabsorption syndrome or other condition that would interfere with enteral absorption 6. Known and untreated, or active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). 7. Uncontrolled pleural effusion or ascites requiring recurrent drainage procedures twice per month or more frequently 8. Any active infection that, in the opinion of the investigator, could impact patient safety; or, serious infection requiring IV antibiotics within 7 days prior to Day 1 of Cycle 1 9. Any concurrent ocular or intraocular condition (e.g., cataract or diabetic retinopathy) that, in the opinion of the investigator or study ophthalmologist, would require medical or surgical intervention during the study period to prevent or treat vision loss that might result from that condition 10. Active inflammatory (e.g., uveitis or vitritis) or infectious (e.g., conjunctivitis, keratitis, scleritis, or endophthalmitis) conditions in either eye or history of idiopathic or autoimmuneassociated uveitis in either eye 11. Patients requiring any daily supplemental oxygen 12. History of or active inflammatory disease (e.g., Crohn’s disease or ulcerative colitis), or any active bowel inflammation (including diverticulitis). Patients currently receiving immunosuppressants (e.g., sulfasalazines) are considered to have active disease; therefore, they are ineligible. 13. Symptomatic hypercalcemia requiring continued use of bisphosphonate or denosumab therapy 14. Clinically significant history of liver disease, including severe liver impairment (Child-Pugh Class B/C), viral or other hepatitis, current alcohol abuse, or cirrhosis 15. Known HIV infection 16. Any other diseases, active or uncontrolled pulmonary dysfunction, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, that may affect the interpretation of the results, or renders the patients at high risk from treatment complications 17. Significant traumatic injury or major surgical procedure within 4 weeks prior to initiation of study treatment 18. Radiation therapy (other than palliative radiation to bony metastases) as cancer therapy within 4 weeks prior to initiation of study treatment 19. Palliative radiation to bony metastases within 2 weeks prior to initiation of study treatment 20. Unresolved toxicity from prior therapy, except for the following: Alopecia Grade 1 and peripheral neuropathy 21. Inability to comply with study and follow-up procedures 22. History of other malignancy within 5 years prior to screening, with the exception of patients with a negligible risk of metastasis or death and/or treated with expected curative outcome (such as appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer) 23. History of or active ventricular dysrhythmias or congestive heart failure requiring medication or coronary heart disease that is symptomatic 24. Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia) 25. Congenital long QT syndrome or QT interval corrected with Fridericia’s formula (QTcF) 470 ms demonstrated by at least two ECGs 30 minutes apart, or family history of sudden unexplained death or long QT syndrome 26. Current treatment with medications that are well known to prolong the QT interval 27. Allergy or hypersensitivity to components of the inavolisib formulation and paclitaxel 28. Pregnancy, lactation, or intention to become pregnant or fathering a child during the study 29. Women of childbearing potential (including those who have had a tubal ligation) must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. Exclusion Criteria Specific to Patients Enrolling Part 1, Arm A: 1. History of prior significant toxicity related to a PI3K, AKT, or mTOR inhibitor requiring discontinuation of treatment. Patients may have received prior treatment with a PI3K, AKT, or mTOR inhibitor 2. History of prior significant toxicity related to paclitaxel treatment requiring discontinuation of treatment. Patients may have received prior treatment with paclitaxel 3. Treatment with chemotherapy, immunotherapy, or biologic therapy as anti-cancer therapy within 21 days prior to initiation of study treatment, except for the following: Kinase inhibitors, approved by regulatory authorities, may be used up to 2 weeks prior to initiation of study treatment, provided any drug-related toxicity has resolved up to Grade 1 and prior approval is obtained from the Medical Monitor. Treatment with an investigational agent within 3 weeks or five half-lives prior to initiation of study treatment, whichever is shorter. A shorter washout period may be allowed if the patient has adequately recovered from any clinically relevant toxicity and with prior approval from the Medical Monitor. 4. Prior anti-cancer therapy that fulfills the following criteria: High dose chemotherapy requiring stem-cell support; Irradiation to 25% of bone marrow-bearing areas Exclusion Criteria Specific to Patients Enrolling Part 2, Arm A: 1. History of prior significant toxicity related to a PI3K, AKT, or mTOR inhibitor requiring discontinuation of treatment. 2. Prior treatment with any PI3K-specific inhibitor 3. History of prior significant toxicity related to paclitaxel treatment requiring discontinuation of treatment. Patients may have received prior treatment with paclitaxel 4. Treatment with chemotherapy, immunotherapy, or biologic therapy as anti-cancer therapy within 21 days prior to initiation of study treatment, except for the following: Kinase inhibitors, approved by regulatory authorities, may be used up to 2 weeks prior to initiation of study treatment, provided any drug-related toxicity has resolved up to Grade 1 and prior approval is obtained from the Medical Monitor Treatment with an investigational agent within 3 weeks or five half-lives prior to initiation of study treatment, whichever is shorter 5. Prior anti-cancer therapy that fulfills the following criteria: high dose chemotherapy requiring stem-cell support Irradiation to 25% of bone marrow-bearing areas Removed 20/07/2022: Exclusion Criteria Specific to Patients Enrolling Part 2, Arm B: 1. Prior treatment with any PI3K, AKT, or mTOR inhibitor, or any agent whose mechanism of action is to inhibit the PI3K/AKT/mTOR pathway 2. Any prior systemic anti-cancer therapy for locally advanced or metastatic HER2-positive breast cancer prior to initiation of study treatment 3. Current uncontrolled hypertension (systolic blood pressure over 150 mmHg or diastolic blood pressure over 100 mmHg) or unstable angina 4. History of congestive heart failure (CHF) of New York Heart Association (NYHA) classification Class II or higher, or serious cardiac arrhythmia requiring treatment (excluding atrial fibrillation or paroxysmal supraventricular tachycardia) 5. History of myocardial infarction within 6 months prior to initiation of study treatment 6. History of LVEF decline to below 40% during or after prior treatment with trastuzumab 7. History of exposure to cumulative dose of doxorubicin (or equivalent anthracycline exposure) 360 mg/m² of body surface area or its equivalent 8. Symptomatic active lung disease, including pneumonitis or interstitial lung disease 9. History of prior significant toxicity related to paclitaxel, trastuzumab or pertuzumab requiring discontinuation of treatment
Date of first enrolment	26/07/2021
Date of final enrolment	30/11/2024

Locations

Countries of recruitment

Brazil
Canada
Denmark
France
Korea, South
Spain
United States of America

Study participating centres

Florida Cancer Specialist-Lake Mary

805 Currency Circle
Lake Mary
32746
United States of America

Rigshospitalet

Fase 1 Enhed - Onkologi
Juliane Maries Vej 6
Opgang 5, 1. sal, Afsnit 5011
København Ø
2100
Denmark

Centre Leon Berard

Departement Oncologie Medicale
28 Rue Laennec
CEDEX 08
Lyon
69008
France

Institut Bergonie

Oncologie
229 Cours de L'Argonne
Bordeaux
33076
France

Samsung Medical Center

81, Irwon-Ro, Gangnam-gu
Seoul
(0)6351
Korea, South

Seoul National University Hospital

101, Daehakro
Jongno-gu
Seoul
03080
Korea, South

Hospital Clinico Universitario de Valencia

Servicio de Onco-hematologia
Avenida Blasco Ibañez, 17
Valencia
46010
Spain

Hospital Univ Vall d'Hebron

Servicio de Oncologia
Passeig De La Vall D'hebron 119-129
Barcelona
08035
Spain

Massachusetts General Hospital

55 Fruit Street
Boston
02114
United States of America

Sarah Cannon Cancer Center - Tennessee Oncology, PLLC

250 25th Ave North
Suite 312
Nashville
37203
United States of America

Jewish General Hospital

3755 Côte Ste Catherine Road
Montreal
H3T 1E2
Canada

Princess Margaret Cancer Centre

700 University Avenue 7th Floor
7723
Toronto
M5G 1Z5
Canada

START Madrid. Centro Integral Oncologico Clara Campal; CIOCC

-
Madrid
28050
Spain

Clinica de Pesquisa e Centro de Estudos em Oncologia Ginecologica e Mamaria Ltda

Sao Paulo
01317-001
Brazil

Núcleo de Pesquisa São Camilo; Oncologia Clinica/Quimioterapia

Sao Paulo
04014-002
Brazil

Hospital Sao Lucas - PUCRS

Porto Alegre
90610-000
Brazil

Hospital das Clinicas - UFRGS

Porto Alegre
90035-903
Brazil

Avera Cancer Institute

Sioux Falls
57105
United States of America

Hospital do Cancer de Pernambuco - HCP

Recife
50040-00
Brazil

Hospital Nossa Senhora da Conceicao

Porto Alegere
90040-373
Brazil

Sponsor information

Genentech, Inc
Industry

1 DNA Way
South San Francisco
94080
United States of America

Phone	+1 (0)888 662 6728
Email	global-roche-genentech-trials@gene.com
Website	https://www.roche.com/about_roche/roche_worldwide.htm

Funders

Funder type

Industry

Genentech
Private sector organisation / For-profit companies (industry)

Alternative name(s): Genentech, Inc., Genentech USA, Inc., Genentech USA
Location: United States of America

Results and Publications

Intention to publish date	30/07/2025
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not expected to be made available
Publication and dissemination plan	Planned publication in a high-impact peer-reviewed journal. No additional study documents will be made available.
IPD sharing plan	Participant level data is not expected to be made available. This is not a regulatory requirement and typically not disclosed for Phase I studies.

Editorial Notes

19/09/2024: The following changes were made:
1. START Madrid. Centro Integral Oncologico Clara Campal; CIOCC, Clinica de Pesquisa e Centro de Estudos em Oncologia Ginecologica e Mamaria Ltda, Núcleo de Pesquisa São Camilo; Oncologia Clinica/Quimioterapia, Hospital Sao Lucas - PUCRS, Hospital das Clinicas - UFRGS, Avera Cancer Institute, Hospital do Cancer de Pernambuco - HCP and Hospital Nossa Senhora da Conceicao were added as study participating centres.
2. Brazil was added to the countries of recruitment.
27/08/2024: The following changes were made to the trial record:
1. The recruitment end date was changed from 09/05/2023 to 30/11/2024.
2. The overall end date was changed from 30/07/2024 to 30/10/2025.
3. The plain English summary was updated to reflect these changes.
05/12/2023: Study website added.
20/07/2022: The following changes were made to the trial record:
1. The public title was changed from 'A study to evaluate the safety, tolerability, processing by the body, and antitumor activity of inavolisib and paclitaxel with or without targeted therapies' to 'A study to evaluate the safety, tolerability, processing by the body, and antitumor activity of inavolisib and paclitaxel'.
2. The scientific title was changed from 'A Phase Ib, open-label, dose-escalation and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of inavolisib in combination with paclitaxel and with or without targeted therapies in patients with locally advanced or metastatic solid tumors' to 'A Phase Ib, open-label, dose-escalation and dose-expansion study evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of inavolisib in combination with paclitaxel in patients with locally advanced or metastatic solid tumors'.
3. The study hypothesis, interventions, secondary outcome measures, inclusion and exclusion criteria and plain English summary were updated.
4. Trastuzumab and pertuzumab were removed from the drug names.
5. The target number of participants was changed from 120 to 104.
6. The trial participating centres were updated to remove Institut Claudius Regaud, START Madrid and MaRS Centre and add Princess Margaret Cancer Centre.
21/06/2021: Trial's existence confirmed by Mass General Brigham Institutional Review Board.