IRB Study Number 24-132
Status Recruiting
Institute Taussig Cancer Institute
Description
Phase 1a Dose Escalation BBO-8520 Monotherapy
Primary Objectives
· To evaluate the safety and tolerability of escalating doses of BBO-8520 in subjects with locally advanced and unresectable or metastatic (ie, advanced) NSCLC with a KRASG12C mutation.
Secondary Objectives
· To evaluate preliminary antitumor activity of BBO-8520.
· To characterize the pharmacokinetics (PK) of BBO-8520.
· To evaluate the effect of food on the oral PK properties of BBO-8520
Phase 1a Dose Escalation BBO-8520 + Pembrolizumab Combination Therapy
Primary Objectives
· To determine the optimal dose of BBO-8520 administered in combination with pembrolizumab in Phase 1b Dose Expansion by evaluation of totality of safety, PK, and efficacy data.
Secondary Objectives
· To evaluate preliminary antitumor activity of BBO-8520.
Inclusion Criteria
Age:
- Subjects must be ≥18 years old at signing of informed consent.
Type of Subject and Disease Characteristics:
- Have histologically documented, locally advanced and unresectable, or metastatic (ie, advanced) NSCLC with a KRASG12C mutation:
a. Documentation of KRASG12C mutation:
− Local documentation, as evidenced by a laboratory test report is sufficient for study entry.
− For subjects without prior documentation of KRASG12C mutation:
○ prospective confirmation of KRASG12C tumor mutational status is required based on sponsor-provided central testing (see Section 8.2).
○ enrollment based upon results of a newly performed local test may be allowed after approval by the medical monitor.
b. Except for Dose Escalation cohorts (BBO-8520 monotherapy and BBO-8520 + pembrolizumab combination therapy), subjects with G12D, G12V, M72K, Q61H, R164Q, R68S, and T2S co-alterations in KRAS (when reported) will be excluded.
c. Must have no other targetable driver mutations (eg, epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK], ROS1/BRAF/RET/MET/EGFR exon 20 insertion/NTRK/HER2).
d. In locally advanced and unresectable disease, progression on or within 6 months of the end of prior multimodal therapy with curative intent will count as a prior line of therapy.
Have measurable disease by RECIST v1.1.
Have a minimum life expectancy of >12 weeks according to the investigator’s judgement.
Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score 0 or 1 (see Section 8.4.6).
Are willing and able to comply with study visits and study procedures.
Sex and Contraceptive/Barrier Requirements:
- Contraceptive use by study participants should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. Male subjects: Male subjects are eligible to participate if they agree to the following during the study treatment period and for at least 120 days after the last dose of study drug:
• Refrain from donating sperm
PLUS, either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR
• Must agree to use contraception as detailed below:
− Agree to use a male condom (with female partner use of an additional highly effective contraceptive method with a failure rate of <1% per year as described in Section 10.4, Contraceptive and Barrier Guidance) when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant.
− Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.
b. Female subjects: A female participant is eligible to participate if she is not pregnant or breastfeeding, or planning to become pregnant or breastfeed, and one of the following conditions applies:
• Is a woman of nonchildbearing potential (refer to Section 10.4.1). OR
• Is a WOCBP (Section 10.4.1) and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, as described in in Section 10.4, Contraception and Barrier Guidance, during the study treatment period and for at least 90 days after the last dose of study drug and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the potential for contraceptive method failure (eg, noncompliance, recently initiated) in relationship to the first dose of study drug.
• A subject who is a WOCBP must have a negative highly sensitive serum pregnancy test during screening and within 48 hours before the first dose of study drug.
Additional requirements for pregnancy testing during and after study treatment are presented in Section 8.4.5.
The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent:
- Subjects must be capable of giving signed informed consent as described in Section 10.1.3.2, which includes compliance with the requirements and restrictions listed in the ICF (molecular prescreening and/or main study ICF) and in this protocol.
Subjects Enrolled in Phase 1a Dose Escalation BBO-8520 Monotherapy Cohorts Only
- Have progression on or disease recurrence after available standard of care treatments, which must include an ICI (unless contraindicated). Subjects must have received prior standard therapy, or in the opinion of the investigator, would be unlikely to tolerate or derive clinically meaningful benefit from appropriate standard of care therapy.
a. Prior treatment with a KRASG12C(OFF) inhibitor (eg, sotorasib, adagrasib, JDQ443, LY3537892, GDC-6036) is allowed but not required.
- For subjects enrolled for food effect assessment:
a. Able to eat a standardized high-fat, high-calorie meal within 25 minutes.
b. Able to fast for ≥13 hours.
Subjects Enrolled in Phase 1a Dose Escalation BBO-8520 + Pembrolizumab Combination Therapy Cohort(s) Only
- No prior therapy for locally advanced and unresectable or metastatic NSCLC as follows:
a. No prior treatment with a KRASG12C inhibitor.
b. No prior treatment with an ICI (eg, pembrolizumab, atezolizumab, nivolumab, ipilimumab, durvalumab).
c. Neoadjuvant or adjuvant platinum-based doublet chemotherapy and/or ICI are allowed if treatment was completed >12 months prior to screening.
d. Tumor proportion score (TPS) of ≥50%.
Subjects Enrolled in Phase 1b Randomized Dose Optimization BBO-8520 Monotherapy Cohorts Only
- Have progression on or disease recurrence after at least 1 prior line of systemic therapy, which must include platinum-based doublet chemotherapy, ICI, or both given together as 1 line or as individual lines of therapy.
a. No prior treatment with a KRASG12C inhibitor (unless the SRC recommends that subjects who have received prior treatment with a KRASG12C(OFF) inhibitor may be allowed into these cohorts after review of emerging PK, PD/biomarker, efficacy, and safety data from the monotherapy dose escalation part of the study).
Subjects Enrolled in Phase 1b Dose Expansion Cohorts Only
- Dose Expansion BBO-8520 Monotherapy Cohort (no prior KRASG12C inhibitor): have progression on or disease recurrence after at least 1 prior line of systemic therapy, which must include platinum-based doublet chemotherapy, ICI, or both given together as 1 line or as individual lines of therapy.
a. No prior treatment with a KRASG12C inhibitor.
- Dose Expansion BBO-8520 Monotherapy Cohort (prior KRASG12C(OFF) inhibitor): have progression on or had disease recurrence after a KRASG12C(OFF) inhibitor (eg, sotorasib, adagrasib, JDQ443, LY3537892, GDC-6036). Prior interim therapy (eg, docetaxel) is allowed.
a. Prior therapy must have included an ICI (eg, pembrolizumab, atezolizumab, nivolumab ± ipilimumab, durvalumab ± tremelimumab, cemiplimab-rwlc).
- Dose Expansion BBO-8520 + pembrolizumab Combination Therapy Cohort: no prior therapy for locally advanced and unresectable or metastatic NSCLC.
a. No prior treatment with any KRASG12C inhibitor.
b. No prior treatment with an ICI (eg, pembrolizumab, atezolizumab, nivolumab, ipilimumab, durvalumab). -Neoadjuvant or adjuvant platinum-based doublet chemotherapy and/or ICI are allowed if treatment was completed >12 months prior to screening.
c. TPS of ≥50%.
Exclusion Criteria
All Subjects
Medical Conditions:
- Have inadequate organ function as defined below:
Hematological:
Absolute neutrophil count (ANC) <1,500/μL
b. Platelets <100,000/μL
c. Hemoglobin <9 g/dL without transfusion for at least 2 weeks prior to enrollment
d. Hemoglobin <9 g/dL without erythropoiesis-stimulating agents (eg, Epo, Procrit®) for at least ≤6 weeks prior to enrollment
Renal:
e. Creatinine clearance <50 mL/min (measured or calculated using the Cockcroft-Gault formula: (140 – age) × (weight in kg) × (0.85 if female) / 72 × (serum creatinine in mg/dL)
Hepatic
f. Serum total bilirubin >1.5 × institutional ULN or ≥2.0 × ULN if the subject has a diagnosis of Gilbert syndrome
g. AST/serum glutamic-oxaloacetic transaminase (SGOT) and/or ALT/serum glutamic-pyruvic transaminase (SGPT) >2.5 × ULN or AST and/or ALT >5.0 × ULN with documented liver metastases.
Coagulation:
h. International normalized ratio (INR) or prothrombin time (PT) >1.5 × ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.
i. aPTT >1.5 × ULN unless the subject is receiving anticoagulant therapy and as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants.
Have active hepatitis B infection (hepatitis B surface antigen [hBsAg] or hepatitis B virus [HBV] DNA), hepatitis C infection (hepatitis C virus [HCV] antibody and positive HCV RNA).
Known positive HIV test.
Have any other life-threatening illness, medical condition, active uncontrolled infection, or organ system dysfunction (such as ascites, coagulopathy, or encephalopathy), or other reasons which, in the investigator’s opinion, could compromise the participating subject’s safety, or interfere with or compromise the integrity of the study outcomes.
Have any of the following cardiac-related issues or findings:
a. History of significant cardiovascular disease, such as cerebrovascular accident, myocardial infarction or unstable angina, within the last 6 months before starting study treatment.
b. Clinically significant cardiac disease, including New York Heart Association Class II or higher heart failure.
c. History of left ventricular ejection fraction (LVEF) <50% within the previous 12 months before starting study treatment.
d. Resting QT interval corrected for heart rate (QTc) >470 msec, derived as the average from 3 ECGs at screening.
e. Any clinically significant abnormalities in rhythm, conduction, or morphology of resting ECG (eg, third degree heart block, Mobitz Type II heart block, ventricular arrhythmias, uncontrolled atrial fibrillation).
f. Subjects with a pacemaker may be allowed on study following review and agreement between the treating physician and medical monitor.
Have a diagnosis of another invasive malignancy within the previous 2 years from time of informed consent other than curatively treated non-melanomatous skin cancer, superficial urothelial carcinoma, in situ cervical cancer, or any other curatively treated or closely monitored malignancy that is not expected to require treatment for recurrence or progress during the course of the study.
Have untreated brain metastases (subjects with stable brain metastases are allowed). Subjects who have had brain metastases resected or have received whole brain radiation therapy ending at least 4 weeks prior to C1D1 or who have received stereotactic radiosurgery ending at least 2 weeks prior to C1D1 are eligible if they are neurologically stable and meet all of the following criteria prior to first dose of study medication: a) residual neurological symptoms related to the CNS treatment Grade ≤2; b) on a stable or decreasing dose of ≤10 mg daily prednisone (or equivalent) for at least 2 weeks prior to C1D1; and c) follow-up magnetic resonance imaging (MRI) shows no new or worsening lesions at least 4 weeks after completion of treatment.
Have clinically significant active gastrointestinal illness or inability to ingest the medication in its intended form that would preclude absorption of BBO-8520 (eg, swallowing issues, post gastrectomy, short bowel syndrome, uncontrolled Crohn’s disease, celiac disease with villous atrophy, or chronic gastritis).
Pregnant or lactating subjects or subjects expecting to conceive children within the projected duration of the trial, starting with the Screening visit through 90 days after the last dose of BBO-8520.
Are on dialysis.
Have a history of allogeneic bone marrow transplant.
Prior/Concomitant Therapy:
Have received prior treatment with a KRASG12C(ON) inhibitor (eg, RMC-6291, FMC-376).
Have undergone major surgery within 4 weeks prior to C1D1.
Note: This does not include subjects who have had procedures such as peripherally inserted central catheter line placement, thoracentesis, paracentesis, biopsies, or abscess drainage.
Have Grade >1 unresolved toxicities) from prior surgery or any anti-tumor therapy with exception of alopecia.
Have participated in an interventional clinical study within the last 4 weeks OR, if applicable, be within 5-times the half-life of the investigational study drug(s), whichever is lesser, prior to the C1D1 visit. Subjects should always adhere to other eligibility criteria that apply to specified concomitant medication regarding washout periods as specified below.
Have received radiotherapy or proton therapy with a limited field of radiation for palliation within 2 weeks of the start of study treatment, OR radiation to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the start of study treatment. Palliative radiotherapy to non-target lesions may be allowed on a case-by-case basis by the medical monitor in consultation with the investigator.
Have taken any of the following (see Section 10.6 for additional details):
a. Strong inducers or inhibitors of CYP3A or P-gp within 14 days or 5 half-lives of the agent (whichever is longer) prior to C1D1, or food products containing the fruit or juice from grapefruit, starfruit, pomegranates, or Seville oranges within 7 days prior to C1D1,
and/or
b. Use of known CYP3A substrates with a narrow therapeutic window, within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to C1D1,
and/or
c. Acid- reducing agents, such as proton pump inhibitors (PPIs) or histamine 2 (H2) receptor antagonists within 3 days of C1D1 and for the study duration.
Have received more than 1 prior line of a KRASG12C(OFF) inhibitor (for subjects in the Dose Expansion cohort in which prior treatment with a KRASG12C(OFF) inhibitor is permitted).
Are planning to receive any other systemic therapy intended to treat NSCLC while on this study.
Other Exclusions:
- Have a history of hypersensitivity to BBO-8520, active or inactive excipients of BBO-8520 or drugs with a similar chemical structure or class to BBO-8520.
Subjects Enrolled in BBO-8520 + Pembrolizumab Combination Therapy Cohorts Only
The following additional exclusion criteria apply to subjects enrolled in BBO-8520 + pembrolizumab combination therapy cohorts in Phase 1a and Phase 1b:
Have experienced Grade ≥3 toxicity deemed related to any prior ICI therapy which required discontinuation.
Have a history of hypersensitivity to pembrolizumab, active or inactive excipients of pembrolizumab, or drugs with a similar chemical structure or class to pembrolizumab.
Have received >30 Gy of radiation to the thoracic region within 24 weeks prior to first dose of study treatment.
Have received any live/attenuated vaccine within 30 days prior to first dose of study treatment. Examples of live vaccines include, but are not limited to, mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed.
Have active autoimmune disease or history of autoimmune disease that might recur, which may affect vital organ function or require immune suppressive treatment including systemic corticosteroids. This includes, but is not limited to, subjects with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn’s, ulcerative colitis, hepatitis; and subjects with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome because of the risk of recurrence or exacerbation of disease.
a. Subjects with vitiligo, endocrine deficiencies including type I diabetes mellitus, thyroiditis managed with replacement hormones including physiologic corticosteroids are eligible.
b. Subjects with rheumatoid arthritis and other arthropathies, Sjögren’s syndrome and psoriasis controlled with topical medication and subjects with positive serology, such as antinuclear antibodies (ANA), anti-thyroid antibodies should be evaluated for the presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible.
Have a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
Have uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; interstitial lung disease (ILD) or active, non-infectious pneumonitis; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements.
Have a condition requiring systemic treatment with either corticosteroids (>10 mg prednisone equivalent) or other immunosuppressive medication within 14 days of C1D1. Steroids with minimal systemic absorption (eg, topical, ocular, intranasal, intraarticular, inhalational), limited course for the treatment of or prophylaxis of hypersensitivity reaction, and adrenal replacement steroids >10 mg prednisone equivalent are permitted in the absence of active autoimmune disease.
Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of suspected immunologic etiology or for chemotherapy premedication as part of treatment on trial. The use of physiologic doses of corticosteroids may be approved after consultation with the medical monitor.
