IRB Study Number 24-746
Status Recruiting
Phase Phase 1
Location Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Primary Objectives
To assess safety and tolerability at increasing dose levels of PF-07934040 in successive cohorts of participants with KRAS mutated tumors in order to estimate the MTDM/RDEM and select the Phase 1 Expansion Dose.
Secondary Objectives
To characterize the single and multiple dose PK of PF-07934040 as monotherapy.
To assess any preliminary anti-tumor activity of PF-07934040 as a monotherapy in participants with advanced solid tumor harboring a KRAS mutation.
To evaluate the effect of food on the PK of PF-07934040 as monotherapy in a subset of participants.
To evaluate the intended MoA modulation of KRAS inhibition by PF-07934040 by PD changes in downstream proximal biomarkers in tumor biopsy samples of participants with advanced solid tumor malignancies.
Inclusion Criteria
Age and Sex:
- 18 years of age or older (or the minimum age of consent in accordance with local regulations) at screening.
Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female (Section 10.4.2) participants.
Disease Characteristics (Applies to All Participants Unless Otherwise Specified):
- Histological or cytological diagnosis of advanced, unresectable, metastatic tumor.
Note for PDAC: Only participants with the histologic type of adenocarcinoma of the pancreas are allowed to enroll. For PDAC, if loco-regional disease is present, must also have metastatic disease.
- Documentation of mutated KRAS gene.
KRAS mutations of any variant except previously treated G12C, present in tumor tissue or blood (eg, ctDNA).
Identification of KRAS mutation by either PCR or NGS-based local laboratory assay obtained in a CLIA or similarly certified laboratory prior to screen.
If the participant received KRAS G12C inhibitor treatment previously, the KRAS mutation status must be other than G12C. This mutation status should be identified after progression on the last therapy undertaken by the participant (a discussion with the sponsor is required if this is not possible).
o Note for NSCLC: If driver mutation, must have failed precision medicine therapy (eg, inhibitors of EGFR, ALK, ROS1, others).
- Part 1 and Part 2a: Participant must have progressed on standard treatment(s) for which no other effective therapy is available.
a. PDAC (2-3L): Participants must have received and radiologically progressed on prior lines of systemic therapy for metastatic pancreatic adenocarcinoma. If participants received prior adjuvant chemotherapy and progressed within 6 months of the last dose, then this treatment is considered as a prior line of systemic therapy.
b. NSCLC (2-3L): Participants must have received prior lines of anti-cancer treatment and progressed on at least a platinum-containing chemotherapy regimen and a checkpoint inhibitor. For participants with EGFR, ALK, or other genomic tumor alterations, participants must have progressed on approved therapy for these alterations.
c. CRC (2-3L): Participants must have had one or two prior systemic treatment regimens for mCRC. For either one or two prior treatments, these regimens must include a fluoropyrimidine, irinotecan and/or oxaliplatin for one prior treatment, exposure to a VEGF/VEGF receptor (VEGFR) inhibitor is optional.
d. Other tumors: In the judgment of the investigator, participants must have progressed or become intolerant to all available standard therapies, or have refused such therapy.
- Part 2b:
a. PDAC (1L) Cohort A2: Participants must not have received prior chemotherapy for metastatic disease. Participant could have received neoadjuvant therapy, adjuvant therapy, or adjuvant chemo-radiotherapy, as long as relapse did not occur within 6 months of completing these forms of adjuvant treatment. If so, the relapse within 6 months would be considered a line of therapy; the participant would be considered 2L, and not 1L.
b. CRC (2-3L) Cohort B2: Participants must have had one or two prior systemic treatment regimens for mCRC. For either one or two prior treatments, these regimens must include a fluoropyrimidine, irinotecan and/or oxaliplatin for one prior treatment, exposure to a VEGF/VEGF receptor (VEGFR) inhibitor is optional.
c. CRC (1L) Cohort B3: Participants must not have received prior chemotherapy for metastatic disease. Participant could have received neoadjuvant therapy, adjuvant therapy, or adjuvant chemo-radiotherapy, as long as relapse did not occur within 6 months of completing these forms of adjuvant treatment. If so, the relapse within 6 months would be considered a line of therapy; the participant would be considered 2L, and not 1L. Note for CRC: Participants known to have MSI-H or dMMR must have previously been treated with a PD-1 inhibitor (eg, pembrolizumab). Participants known to have metastatic CRC with a BRAF V600E mutation must have previously been treated with a BRAF inhibitor (eg, encorafinib).
d. NSCLC (1L) Cohort C2: Participants must have a TPS ≥50%, and must not have received prior systemic treatment for metastatic disease.
e. NSCLC (1L) Cohort C3: Participants may have any TPS (including TPS <1%), and must not have received systemic treatment for metastatic disease setting.
f. Additional Cohort: Indication(s) may be selected and defined based on emerging data from Part 1. These participants will be treated with novel combinations including up to 2 dose levels of the study drug in the novel regimens under study.
Resolution of acute effects of any prior therapy to either baseline severity or CTCAE Grade ≥1 (except for AEs not constituting an ongoing safety risk in the investigator’s judgment).
Presence of at least 1 measurable lesion based on RECIST version 1.1 that has not been previously irradiated.
Able to provide pre-treatment tumor tissue (either recently obtained [within 12 months of Day 1] archival FFPE tumor tissue sample or de novo tumor biopsy collected at screening). If emerging data constitutes the need of a biopsy, this may become mandated by the sponsor at that time. Tissue acquisition details are provided in the Laboratory Manual.
a. Baseline/pre-treatment tumor tissue: All participants must have either recent archival FFPE tumor tissue sample or undergo fresh tumor biopsy collected at screening. If the archival sample is older than 12 months and a pre-treatment fresh de novo biopsy cannot be performed safely, the investigator must contact the sponsor to discuss eligibility prior to enrollment. Fresh de novo biopsy should be restricted to non-target lesion(s) when feasible.
b. On-treatment tumor biopsy: Fresh de novo biopsy should be restricted to nontarget lesion(s) when feasible. If emerging data constitutes the need for a biopsy, this may become mandated by the sponsor at that time. Additionally, paired biopsies are required if enrolled in the mandatory biomarker cohort at the RDE monotherapy dose expansion (See Section 8.7).
Other Inclusion criteria:
ECOG PS 0 or 1.
Participants with brain metastases must meet all the following conditions:
a. Have completed their planned course of treatment or have brain metastases that are small, stable, and not growing as assessed by the investigator in consultation with the sponsor;
b. Have recovered from the acute effects of radiation therapy or neurosurgery prior to planned first dose (Day 1);
c. Have discontinued corticosteroid treatment for these metastases for at least 4 weeks prior to Day 1;
d. Have been on stable doses of antiseizure medications (if applicable) for at least 3 months. Antiseizure medications must meet any eligibility criteria outlined for concomitant medications in Section 6.9.
e. Are neurologically stable since the conclusion of therapy, as documented by both neurologic and MRI examinations.
f. Participants who are diagnosed with a CNS metastasis during the screening period must also meet these criteria.
Exclusion Criteria
5.2.1. General Exclusion Criteria
Medical Conditions:
Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study.
Pulmonary Inflammation or Fibrosis: Active disease (based on screening assessments or thoracic imaging) requiring treatment with systemic steroid therapy; or history of prior pneumonitis/ILD including pulmonary fibrosis.
Participants with any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell invasive skin cancer, or squamous carcinoma in situ (Bowen’s disease). Participants who have a history of other curatively treated cancers must be discussed and approved by the sponsor prior to consideration for entering the study.
History of venous thromboembolic event <12 weeks prior to starting study treatment.
Lower extremity deep vein thrombosis or pulmonary embolism are excluded from the study, unless the participant is asymptomatic and taking a stable dose of anticoagulant for a minimum of 4 weeks prior to starting study treatment.
Upper extremity catheter-related venous thrombosis is not an exclusion. However, the participants must be on anticoagulation therapy for a minimum of 4 weeks prior to starting study treatment.
Diagnosis of immunodeficiency or an active autoimmune disease that require systemic treatment with chronic systemic steroid therapy (in a dose exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy in the past 2 years. Note Regarding Disease Types: Participants with diabetes type I, controlled asthma, Graves’ disease, Hashimoto’s disease or hypo- or hyperthyroid disease are exceptions and may participate. Note Regarding Replacement Medications: Replacement and symptomatic therapies (eg, levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) are not considered form of immunosuppressive agents and are permitted.
Sensory peripheral neuropathy ≥Grade 2
Active or history of clinically significant GI disease (including but not limited to inflammatory GI disease [eg, ulcerative colitis, Crohn’s disease, inflammatory bowel disease], immune-mediated colitis, peptic ulcer disease, GI bleeding, chronic diarrhea) and other conditions that are unresolved and/or may increase the risk associated with study participation or study treatment administration.
Active bleeding disorder in the past 6 months, including GI bleeding, (as evidenced by hematemesis or melena), or significant hemoptysis.
Prior/Concomitant Therapy:
Current use of any prohibited concomitant medication(s) or unwillingness or inability to use a required concomitant medication(s). Refer to Section 6.9.
Systemic anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to planned first dose (6 weeks for mitomycin C or nitrosoureas). Prior targeted or endocrine therapy require an interval of 2 weeks or 5 half-lives (whichever is shorter) prior to planned first dose.
Major surgery or completion of radiation therapy ≤4 weeks prior to enrollment/randomization or radiation therapy that included >30% of the bone marrow.
History of Grade ≥3 immune mediated or related AE (including AST/ALT elevations that where considered drug related) and CRS that was considered related to prior immune modulatory therapy (eg, immune checkpoint inhibitors, co stimulatory agents) that required immunosuppressive therapy. An exception would be a participant with a history of vitiligo or thyroid dysfunction who has been off immunosuppressive therapy for at least 6 months, upon consultation with sponsor.
Known sensitivity or contraindication to any component of study intervention (PF-07934040, gemcitabine, nab-paclitaxel, cetuximab, bevacizumab, FOLFOX regimen, 5-FU, pembrolizumab, cisplatin, carboplatin, pemetrexed, SHP2, CDK or EGFR).
Prior/Concurrent Clinical Study Experience:
- Administration with an investigational product (drug or vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study medication (whichever is longer). If there is ongoing participation in studies of other investigational products, eg, experimental drugs or vaccines participants may be eligible if they are in the follow-up phase of the trial and meet these criteria: (a) not received treatment within the timeframe specified above, and (b) no procedures will be performed that may interfere with the interpretation of study results using PF-07934040. Prior to enrollment, cases must be discussed with sponsor’s medical monitor to determine eligibility.
Diagnostic Assessments Leading to Exclusion:
Renal impairment as defined as an estimated creatinine clearance <60 mL/min as calculated using Cockcroft-Gault method (see Appendix 2). In equivocal cases, a 24-hour urine collection test can be used to estimate the creatinine clearance more accurately. For eligibility assessment based upon estimated renal function, the higher of the screening and baseline eGFR values may be used.
Hematologic abnormalities defined as:
a. ANC 1,500/mm3 or 1.5 x 109/L
b. Platelets 100,000/mm3 or 100 x 109/L
c. Hemoglobin ≤9 g/dL. Transfusion support is permitted if completed 14 days prior to the start of study treatment and hemoglobin remains ≥9 g/dL at the start of study treatment.
- Hepatic abnormalities defined as:
a. Total serum bilirubin ≥1.5 x ULN unless the participant has documented Gilbert’s syndrome;
b. AST and ALT ≥2.5 x ULN (≥5.0 x ULN if there is liver involvement by the tumor);
c. Alkaline phosphatase ≥2.5 x ULN (≥5 x ULN in case of bone metastasis).
- Participants with active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) known histories of HBV, HCV, HIV or AIDS related illness. Comments regarding specific infections are listed:
a. COVID-19/SARS-CoV-2:
While SARS-CoV-2 testing is not mandated for enrollment, testing should follow local clinical practice. If a participant has a positive test result for SARS-CoV-2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV-2, he/she is excluded but may be rescreened according to protocol requirements for rescreening if the participant subsequently tests negative.
b. History of HIV:
In equivocal cases, participants whose viral load is negative may be eligible. HIV seropositive participants who are otherwise healthy and at low risk for AIDS related outcomes may be eligible after discussion with the sponsor, but AIDS is exclusionary. Potential eligibility for a specific HIV positive candidate should be evaluated and discussed with the sponsor prior to any screening, based on current and past CD4 and T cell counts, history (if any) of AIDS defining conditions (eg, opportunistic infections), and status of HIV treatment. The potential for DDIs will be taken into eligibility consideration.
c. History of HBV/HCV:
Relevant laboratory tests should be performed at screening (see Appendix 2). Refer to CDC website (https://www.cdc.gov/hepatitis/index.htm) for further details.
Participants with a positive HBsAg (ie, either acute or chronic active hepatitis) are excluded.
Participants with HBV antibody positivity indicating immunity, either due to vaccination (eg, HBsAg negative, anti-HBc negative, and anti-HBs positive), or prior natural infection (eg, HBsAg negative, anti-HBc positive, and anti-HBs positive), are eligible.
Participants with negative HBsAg, anti-HBc positive, and anti-HBs negative may be eligible depending on clinical circumstances, and discussion with the sponsor is indicated. In this circumstance testing for HBV PCR is recommended. Participants whose clinical history and profile suggest either low level chronic infection or resolving acute infection should not be considered eligible.
Positive HCV antibody is indicative of infection but may not necessarily render a potential candidate ineligible, depending on clinical circumstances. Discussion with the sponsor is indicated. If exposure to HCV is recent, HCV antibody may not yet be detected. In this circumstance it is recommended to test for HCV RNA.
Baseline standard 12 lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, baseline QTcF >470 ms, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST segment and/or T wave changes suggestive of active myocardial ischemia, second- or third- degree AV block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 470 ms, or QRS complex exceeds 120 ms, the ECG should be repeated twice and the average of the 3 QTcF or QRS complex values should be used to determine the participant’s eligibility. Computer-interpreted ECGs should be overread by an investigator physician experienced in reading ECGs before excluding participants (See Section 8.3.6).
Any of the following in the previous 6 months: myocardial infarction, long QT syndrome, Torsade de Pointes, clinically important atrial or ventricular arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), serious conduction system abnormalities (eg, bifascicular block, 3rd degree AV block), unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF, New York Heart Association class III or IV, cerebrovascular accident, transient ischemic attack, symptomatic pulmonary embolism, and/or other clinical significant episode of thromboembolic disease. Ongoing cardiac dysrhythmias of NCI CTCAE ≥Grade 2, atrial fibrillation of any grade (≥Grade 2 in the case of asymptomatic lone atrial fibrillation). If a participant has a cardiac rhythm device/pacemaker placed and QTcF >470 ms, the participant may be considered eligible. Participants with cardiac rhythm device/pacemaker must be discussed in detail with the sponsor to judge eligibility.
Other Exclusion Criteria:
- Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
5.2.2. Exclusion Criterion in Combination Cohort with Cetuximab
- Known contraindication to receiving cetuximab, including hypersensitivity or toxicity that would suggest an inability to tolerate maximum cetuximab dose of 500 mg/m2.
5.2.3. Exclusion Criteria in Combination Cohort with FOLFOX and Bevacizumab
Urine dipstick for proteinuria 2+. Participants discovered to have ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hours urine collection and must demonstrate ≤1 g protein in 24 hours before starting dosing.
Serum albumin ≤3.0 g/dL
Radiotherapy within 28 days and abdominal/pelvic radiotherapy within 60 days prior to Cycle 1 Day 1, except palliative radiotherapy to bone lesions within 7 days prior to Day 1 of Cycle 1.
Severe, nonhealing or dehiscing wound, active ulcer, or untreated bone fracture
5.2.4. Exclusion Criteria in Pembrolizumab and Pembrolizumab plus Platinum
Chemotherapy Cohorts:
Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear IgA dermatosis toxic epidermal necrolysis and exfoliative dermatitis).
Has participated in any other pembrolizumab trial and has been treated with pembrolizumab. Prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent or an antibody targeting other immune-regulatory receptors or mechanisms. Examples of such antibodies include (but are not limited to) antibodies against IDO, PD-L1, IL-2R, GITR.
Has symptomatic ascites or pleural effusion. A participant who is clinically stable following treatment for these conditions (including therapeutic thoracentesis or abdominal paracentesis) is eligible.
