IRB Study Number 24-894
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
Determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of RO7623066 alone and in combination in patients with advanced solid tumors
Secondary Objectives
Assess the safety and tolerability of RO7623066 alone and in combination in patients with advanced solid tumors
Characterize the PK of RO7623066 alone and in combination in patients with advanced solid tumors
Evaluate preliminary antitumor activity of RO7623066 alone and in combination in patients with advanced solid tumors
To determine the effect of food on the PK of RO7623066 (for Food Effect Cohort)
Inclusion Criteria
Age 18 years or older
Life expectancy of ≥ 12 weeks
Measurable disease or non-measurable disease per RECIST v1.1 (Eisenhauer 2009) in dose escalation and the Food Effect Cohort only; patients in dose expansion and Backfill Cohorts are required to have measurable disease per RECIST v1.1
Recovered to ≤ Grade 1 or baseline toxicity (except alopecia) from prior therapy (per NCI-CTCAE v5.0)
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix 2)
Adequate bone marrow function defined as:
a) absolute neutrophil count of ≥ 1.5 × 109/L
b) platelet count of ≥ 100.0 × 109/L
c) hemoglobin of ≥ 10.0 g/dL (with or without transfusion)
Adequate renal function defined as calculated creatinine clearance (Cockcroft-Gault) ≥ 40 mL/min for patients with creatinine levels above institutional normal
Adequate hepatic function defined as:
a) Total bilirubin ≤ 1.5 × upper limit of normal (ULN) unless associated with Gilbert’s syndrome
b) Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 × ULN (or ≤ 5 × ULN in patients with liver metastases)
Female patients who are women of childbearing potential (WOCP) (defined as physiologically and anatomically capable of becoming pregnant), confirmed of a negative pregnancy test and agreement to the use of a highly effective contraceptive method or at least 2 effective methods at the same time during study treatment period and for up to 3 months after the last dose of study treatment. Male patients must be willing to use effective barrier contraception (ie, condoms) during the study treatment period and for up 3 months after the last dose of study treatment
Capable of understanding and complying with protocol requirements
Signed and dated institutional review board (IRB)/independent ethics committee (IEC) approved informed consent form (ICF) before any protocol-directed Screening procedures are performed
Does not require ongoing treatment with strong or moderate CYP3A4 inhibitors or inducers. See Appendix 1 for further guidance on CYP3A4 inhibitors and inducers
Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumors who meet one of the following criteria (dose escalation only):
a) Relapsed or progressed through standard therapy
b) Have a disease for which no standard effective therapy exists
c) Not a candidate for standard effective therapy
Note: In men with prostate cancer, baseline testosterone levels must also be ≤ 50 ng/dL (≤ 2.0 nM) and surgical or ongoing medical castration must be maintained throughout the duration of the study
7.1.1 Additional Inclusion Criteria for Dose Escalation
RO7623066 Monotherapy Tumor Biopsy Cohort
Have a deleterious mutation (germline or somatic) in one of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
Have tumor tissue that is easily accessible for pre-treatment and on-treatment biopsy in the opinion of the Investigator, and be willing to undergo pre-treatment and on-treatment biopsies per protocol
RO7623066 in Combination Dose Escalation
RO7623066 + OLA:
Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
Locally advanced (unresectable) or metastatic tumors for which PARPi is appropriate, or locally advanced (unresectable) or metastatic tumors that may be sensitive to PARPi (eg, ovarian cancer, TNBC, cholangiocarcinoma, prostate cancer, and pancreatic cancer) 18. At least the first 2 patients per DL must have tumor tissue that is easily accessible for pre-treatment and on-treatment biopsy in the opinion of the Investigator, and be willing to undergo pre-treatment and on-treatment biopsies per protocol.
Note: PARPi naïve and prior PARPi therapy allowed.
RO7623066 + CARBO:
Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
Locally advanced (unresectable) or metastatic tumor for which CARBO is appropriate, or locally advanced (unresectable) or metastatic tumors that may be sensitive to CARBO (eg, non-small cell lung carcinoma [NSCLC], pancreatic cancer, cholangiocarcinoma, bladder cancer, ovarian cancer, and TNBC) 21. At least the first 2 patients per DL must have tumor tissue that is easily accessible for pre-treatment and on-treatment biopsy in the opinion of the Investigator and be willing to undergo pre-treatment and on-treatment biopsies per protocol.
Note: PARPi naïve and prior PARPi therapy allowed.
7.1.2 Additional Inclusion Criteria for Backfill Cohorts 22. Have a deleterious BRCA1 mutation (germline or somatic), as assessed by a CLIA certified or equivalent laboratory. 23. Locally advanced (unresectable) or metastatic tumors for which PARPi is appropriate, or locally advanced (unresectable) or metastatic tumors that may be sensitive to PARPi (eg, ovarian cancer, TNBC, cholangiocarcinoma, prostate cancer, and pancreatic cancer).
Note: PARPi naïve and prior PARPi therapy allowed.
7.1.3 Additional Inclusion Criteria for Food Effect Cohort
Have a deleterious mutation (germline or somatic) in at least one of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
Locally advanced (unresectable) or metastatic tumors for which PARPi is appropriate, or locally advanced (unresectable) or metastatic tumors that may be sensitive to PARPi (eg, ovarian cancer, TNBC, cholangiocarcinoma, prostate cancer, and pancreatic cancer)
7.1.4 Additional Inclusion Criteria for Expansion
RO7623066 in Combination Expansion
RO7623066 + OLA:
HRR+ Ovarian Cancer
Histologically diagnosed recurrent or persistent high grade serous ovarian cancer (including primary peritoneal and/or fallopian tube cancer)
Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
Received prior platinum-based chemotherapy
Note: Patients may have platinum-sensitive or resistant disease. PARPi naïve and prior PARPi therapy allowed.
HRR+ Solid Tumor
Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumor (eg, TNBC, cholangiocarcinoma, endometrial carcinoma, and prostate cancer)
Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
Received prior platinum-based chemotherapy
Note: Patients may have platinum-sensitive or resistant disease . PARPi naïve and prior PARPi therapy allowed
RO7623066 + CARBO:
HRR+ Solid Tumor
Histologically or cytologically confirmed locally advanced (unresectable) or metastatic solid tumor (eg, NSCLC, ovarian cancer, pancreatic cancer, bladder cancer, and TNBC)
Have a deleterious mutation (germline or somatic) in at least 1 of the following genes involved in the HRR pathway (BRCA1, BRCA2, PALB2, RAD51, RAD51B, RAD51C, RAD51D, BARD1, BRIP1, FANCA, and NBN) as assessed by a CLIA-certified or equivalent laboratory
Received at least 1 prior platinum-based chemotherapeutic regimen for management of primary disease
Note: PARPi naïve and prior PARPi therapy allowed
Exclusion Criteria
- Prior anticancer treatment including:
a. Chemotherapy or small molecule-targeted therapy < 2 weeks prior to first dose of study treatment
b. Any antibody therapy < 5 half-lives from first dose of study treatment (or 4 weeks since last therapy, whichever is the shortest)
c. Programmed cell death protein-1 or programmed cell death ligand 1 inhibitor therapy < 4 weeks from first dose of study treatment
d. Invasive surgery requiring general anesthesia < 30 days from first dose of study treatment
e. Chemotherapy with nitrosoureas or mitomycin C < 45 days from first dose of study treatment
f. Radiation therapy (including radiofrequency ablation) < 4 weeks prior to initiation of study treatment
Note: Prior stereotactic body radiation therapy or local palliative radiation is allowed < 2 weeks prior to first dose of study treatment
Ongoing Grade 2 or greater toxicity, except alopecia, related to any prior treatment (ie, chemotherapy, targeted therapy, radiation, or surgery)
Prolongation of QT/QTc interval (QTc interval > 480 msec) using the Frederica method of QTc analysis
Women who are pregnant or nursing
Seropositive for human immunodeficiency virus (HIV) 1 or 2 or acquired immunodeficiency syndrome or active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) (Note: Patients with positive HCV antibody may be eligible if HCV ribonucleic acid [RNA] is undetectable on a quantitative HCV RNA assay, the Medical Monitor is available for advice)
Primary malignant brain tumor
Symptomatic and/or untreated brain metastases, active leptomeningeal disease, or central nervous system malignant disease requiring steroids or other therapeutic intervention
Note: Patients with definitively treated brain metastases will be considered for enrollment after seeking advice from the Medical Monitor and must be clinically stable for ≥ 2 weeks prior to the start of treatment
Previous solid organ or hematopoietic cell transplant
Need for treatment with steroids at stable doses (> 10 mg prednisone or equivalent per day). Note: Oral steroids up to 10 mg/day, topical, ophthalmic, or inhaled steroid medications are allowed
Uncontrolled hypertension > 150/100 mm Hg despite aggressive therapy
Concurrent participation in any other investigational therapeutic study
History of stroke, transient ischemic attack, unstable angina, or myocardial infarction within 3 months prior to first dose of study treatment 13. Unable to swallow whole tablets or capsules. Nasogastric or gastric-tube (G-tube) administration is not allowed 14. GI disease that would impair ability to swallow, retain, or absorb drug is not allowed
Uncontrolled concurrent disease or illness including but not limited to:
a. Symptomatic congestive heart failure according to New York Heart Association (NYHA) classification, Class III or IV (per NYHA Classification) unstable angina pectoris, or clinically significant cardia arrhythmia
b. Diabetes mellitus (ie, fasting blood glucose > 220 despite acceptable chronic diabetes therapy)
c. Psychiatric illness that would limit compliance with study requirements, as determined by the Investigator
Other severe, acute, or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of the study results, and in the judgment of the Investigator, would make the patient inappropriate for the study
Known hypersensitivity to any component of RO7623066 or excipient
History of and/or ongoing adrenal disorder (eg, Cushing’s disease, Addison’s disease, adrenal gland suppression)
Suspected pneumonitis or interstitial lung disease (confirmed radiography or by computed tomography [CT]) or a history of pneumonitis or interstitial lung disease in the last 6 months
Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, or other cancer for which the patient has been disease-free for at least 2 years
Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), or baseline features suggestive of MDS or AML on peripheral blood smear or bone marrow biopsy
Treatment with strong or moderate CYP3A4 inhibitors or inducers for a period of 5 half-lives of the inhibitor or inducer prior to the first dose of RO7623066. See Appendix 1 for further guidance on CYP3A4 inhibitors and inducers
Blood transfusions within 4 weeks prior to Screening
7.2.1 Additional Exclusion Criteria for Dose Escalation
7.2.1.1 RO7623066 in Combination Dose Escalation
RO7623066 + OLA:
Prior severe toxicity associated with PARPi treatment (eg, requiring treatment discontinuation or dose reduction/interruption due to severe hematological toxicity within 12 months prior to screening).
Known hypersensitivity to study therapies and its excipients
RO7623066 + CARBO:
Prior severe toxicity (eg, requiring treatment discontinuation) with CARBO
Known hypersensitivity to study therapies and its excipients
7.2.2 Additional Exclusion Criteria for Food Effect Cohort
Subjects taking drugs that can alter the absorption of other drugs by affecting gastrointestinal motility or by changing the gastric pH, as well as drugs that can increase or decrease the metabolism and excretion of the investigational drug.
Known hypersensitivity to study therapies and its excipients
7.2.3 Additional Exclusion Criteria for Expansion
RO7623066 in Combination Expansion
RO7623066 + OLA:
HRR+ Ovarian
Discontinued from prior PARPi therapy due to severe toxicity
Known hypersensitivity to study therapies and its excipients
HRR+ Solid Tumor
HRR+ ovarian cancer
Known hypersensitivity to study therapies and its excipients
RO7623066 + CARBO:
Prior severe toxicity (eg, requiring treatment discontinuation) with CARBO
Known hypersensitivity to study therapies and its excipients
