IRB Study Number 22-1243
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To assess the safety and tolerability of PF-07799544 at increasing dose levels and to estimate the MTD and select the MTDM/RDEM as a single agent in participants with advanced solid tumors.
Secondary Objectives
To characterize the single and multiple-dose PK of PF-07799544 as a single agent
To evaluate preliminary antitumor activity of PF-07799544 as a single agent
Reference: noveltc
Inclusion Criteria
Age and Sex:
- Participants aged 18 years 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.
Adolescent participants aged 16 years and older (at the time of informed consent/assent) with body weight ≥40 kg may be enrolled after initial adult PK and toxicity data are obtained. Admission of adolescents to the study will be as appropriate according to institutional approvals.
Other Inclusion criteria:
ECOG PS 0 or 1. (ECOG PS 2 may be enrolled if the decreased performance status is documented to be due to underlying cancer and with sponsor approval).
Adequate bone marrow function, defined as:
a. ANC ≥1,250/mm3 or 1.25 x 109/L;
b. Platelets ≥75,000/mm3 or 75 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.
Adequate renal function, 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.
Adequate liver function, 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;
c. Alkaline phosphatase ≤2.5 x ULN (≥5 x ULN in case of bone metastasis).
- Resolution of acute effects of any prior therapy to either baseline severity or CTCAE Grade ≤1:
Except for AEs not constituting a safety risk in the investigator’s judgment (eg, alopecia).
Exception is grade 1 or 2 endocrinopathies due to prior immune therapy.
Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations (including Contraceptive and Barrier Guidance outlined in Appendix 10.4), and other study procedures.
Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the ICD and in this protocol. For adolescent participants: The investigator, or a person designated by the investigator, will obtain written informed consent from each study participant’s legal guardian (as defined in Appendix 1 [and the participant’s assent, when applicable,]) before any study-specific activity is performed (unless a waiver of informed consent/assent has been granted by an IRB/EC). All legal guardians should be fully informed, and participants should be informed to the fullest extent possible, about the study in language and terms they are able to understand. The investigator will retain the original copy of each participant's signed consent/assent document.
For participants vaccinated during or prior to the screening period, vaccine related adverse events will have resolved completely.
Inclusion Criteria specific to Phase 1a:
Disease Characteristics:
Histological or cytological diagnosis of advanced/metastatic solid tumor progressed on last prior therapy, without acceptable alternative treatment option.
Measurable target lesion(s) by appropriate imaging criteria or disease present but no measurable target lesion(s).
Brain involvement must meet the following criteria:
Brain metastases or primary brain tumor, whether treated or untreated, must be ≤4.0 cm.
Previously treated brain metastases/primary brain tumor may be stable or progressed since prior local therapy, provided that clinical investigator confirms/documents, there is no clinical indication for immediate re-treatment with local therapy
Initially during Phase 1a, brain involvement must have been previously treated with local therapy (ie surgery, radiation) and asymptomatic (ie, not requiring local therapy or new or increased dose of medications such as steroids or anti-epileptics) in the brain for at least 14 days prior to start of study treatment. Anti-seizure medications must meet any eligibility criteria outlined for concomitant medications (See Appendix 9 and Appendix 12 for allowed/prohibited concomitant medications, including epileptic therapy).
Once PK data shows sufficient coverage of MAPK alteration/mutation in the plasma, participants with progressive or symptomatic and/or untreated brain metastases are eligible. Sufficient coverage defined as: 50% of participants have peak steady-state concentrations above IC50.
- Documentation of MAPK pathway alteration status (ie, present or not present).
If tumor or ctDNA mutation testing has been done previously, the results of such testing must be documented in the eCRF (including specific assay, assay type (eg, PCR or NGS), lab where test was performed, lab certification (eg, CLIA or similar), specific gene(s), and mutation(s) present). In situations where such documentation is incomplete or unclear, the sponsor may request submission of redacted, password protected copies of mutation reports for confirmation of mutation status. Participants in Phase 1a are eligible irrespective of MAPK alteration test results. Requirements for the presence of specific mutation(s) and their documentation in Phase 1b are specified within each substudy.
- Prior to enrollment, confirmed availability of adequate archival tumor tissue. If archival tumor tissue is not available, provision of newly collected tissue/blood acceptable for retrospective analysis of mutation status would satisfy eligibility.
Archival tissue must be of sufficient quantity and quality (see Section 8.8.1) and be obtained within the last 6 months, irrespective of timing of treatment with MAPK pathway inhibitor-based therapy (if previously given). Adequate is defined as: FFPE block or a minimum of 15 unstained slides with >20% tumor nuclei. For all fresh biopsies performed, 6 core biopsies should be attempted with a minimum of 3 cores submitted. The biopsy should be taken from a nontarget lesion when possible. If not available, then a fresh tissue biopsy is required, if able to be performed safely in the opinion of the investigator. If adequate tissue is not available and cannot safely be obtained, participants may be enrolled with prior sponsor approval if they meet all other eligibility criteria. In these situations, any available archival tissue (eg obtained >6 months prior and/or after the most recent MAPKi treatment) should be submitted.
Exclusion Criteria
Medical Conditions:
Brain metastasis/primary brain tumor requiring immediate local intervention (surgery, radiosurgery) in the opinion of the investigator.
Participants with any other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ, Bowen’s disease, prostate intraepithelial neoplasm and ≤6 Gleason grade prostate cancer. Participants with a history of other curatively treated and/or indolent cancers that do not interfere with required radiographic imaging of the primary cancer must be approved by the sponsor prior to entering the study.
Participants with active, uncontrolled bacterial, fungal, or viral infection, including (but not limited to) HBV, HCV, and known HIV or AIDS-related illness. Comments regarding specific infections follow.
a. COVID-19/SARS-CoV2: This protocol excludes participants with active infections, as noted above. While SARS-CoV2 testing is not mandated for entry into this protocol, testing should follow local clinical practice standards. If a patient has a positive test result for SARS-CoV2 infection, is known to have asymptomatic infection or is suspected of having SARS-CoV2, he/she is excluded but may be rescreened according to protocol requirements for rescreening if the participant subsequently tests negative.
b. 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 could be considered eligible. Potential eligibility for a specific HIV positive protocol 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. Also, the potential for DDIs will be taken into consideration.
c. 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.
HBV:
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, positive anti-HBcAb, and negative antiHBsAb may be eligible depending on clinical circumstances, and discussion with the sponsor is indicated. Participants whose clinical history and profile suggest either low level chronic infection or resolving acute infection should not be considered eligible.
HCV:
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. Refer to CDC website for further details (https://www.cdc.gov/hepatitis/hcv/pdfs/hcv_graph.pdf).
- History of venous thromboembolic event <12 weeks prior to starting study treatment.
Lower extremity deep vein thrombosis or pulmonary embolism that does not result in hemodynamic instability, are exceptions and are permitted as long as the participant is stable, asymptomatic and on a stable dose of anticoagulant for a minimum of 4 weeks prior to starting study treatment (C1D1).
Upper extremity catheter-related venous thrombosis is not considered a thromboembolic event for this trial and is not an exclusion.
Known or suspected hypersensitivity to active ingredient/excipients.
Active inflammatory gastrointestinal disease, history of inflammatory bowel disease, chronic diarrhea, previous gastric resection or lap band surgery or inability to swallow and retain study treatment.
Known history of chronic pancreatitis and/or treatment-related pancreatitis (acute or chronic).
Concurrent neuromuscular disorder that is associated with elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
History or current evidence of RVO or current risk factors for RVO (eg, uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes); history of retinal degenerative disease.
History of interstitial lung disease or Grade ≥2 pneumonitis.
Other 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.
Prior/Concomitant Therapy:
Current use of any prohibited concomitant medication(s). Refer to Section 6.9 and Appendix 9. Participants at risk of significant tumor flare or with progression after discontinuation of last prior therapy within these time frames may be allowed within a shorter time frame if a compelling clinical rationale is provided by the investigator and approved by the sponsor.
Systemic anti-cancer therapy (approved or investigational) ongoing at the time of study entry (Day 1). (Refer to Inclusion criteria #6, #10, Exclusion criterion #12, and Section 8.1.1 (documentation of previous anti-cancer therapy). Exceptions include:
Hormone therapy, if consistent with inclusion/exclusion criteria, concomitant therapy and supportive care guidelines (see Section 6.9), may be allowed if approved by the sponsor.
- Surgery:
Major surgery (eg, inpatient procedure with general anesthesia) within 28 days prior to study entry.
Minor surgical procedure or craniotomy within 14 days prior to study entry.
Ongoing surgery-induced complications.
Unresolved, clinically significant sequela of surgery including neurological sequelae from brain/spinal surgery (Anti-seizure medications must meet any eligibility criteria outlined for concomitant medications (See Appendix 9 or Appendix 12 for allowed/prohibited concomitant medications, including epileptic therapy).
*Biopsy is not considered a surgical procedure.
- Radiation therapy:
Full-Dose, external beam radiation therapy within 14 days prior to study entry.
Ongoing radiation-induced complications.
Unresolved, clinically significant sequela of radiation including neurological sequelae from brain/spinal radiation (Anti-seizure medications must meet any eligibility criteria outlined for concomitant medications (See Section 10.9 Appendix 9 for allowed/prohibited concomitant medications, including epileptic therapy).
Prior/Concurrent Clinical Study Experience:
- Ongoing participation in a different clinical trial. A participant may be eligible if they are in the follow-up Phase of a different investigational study and meet the requirements for prior investigational drug treatment as specified above. Cases must be discussed with sponsor’s medical monitor to judge eligibility.
Diagnostic Assessments:
Serum or urine pregnancy test (for females of childbearing potential) positive at Screening.
Impaired cardiovascular function or clinically significant cardiovascular disease or arterial thrombotic disease including, but not limited to, the following:
Screening 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results. Examples include: screening or baseline (ie, C1D1 pre-dose) QTcF interval >470 msec, baseline QRS >120 msec, complete LBBB, signs of an acute or indeterminate age myocardial infarction, ST-T interval changes suggestive of active myocardial ischemia, second- or third degree AV block, or serious bradyarrhythmias or tachyarrhythmias. The QT interval should be rate corrected using the Fridericia method and the resulting QTcF should be used for decision making and reporting. If QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS values should be used to determine the participant’s eligibility (in addition, the QTcF should be <470 msec on at least 2 individual ECGs). If more than 3 ECGs are performed, this should be reviewed with the sponsor’s medical monitor to confirm eligibility. Computer interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants. Such cases must be discussed in detail with sponsor’s medical monitor to judge eligibility. If a participant has a cardiac rhythm device/pacemaker placed and QTcF >470 msec or cannot be accurately determined, the participant must be discussed in detail with sponsor’s medical monitor to judge eligibility.
Any of the following in the previous 6 months: myocardial infarction, long QT syndrome, Torsade de Pointes, clinical important atrial or ventricular arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), unstable angina, coronary/peripheral artery bypass graft, New York Heart Association CHF class ≥ II, cerebrovascular accident, transient ischemic attack, arterial thrombotic event. Arterial thrombotic event requiring the use of thrombolytic agent.
New serious conduction system abnormalities (eg, left anterior hemiblock) which has occurred within the last 6 months, and/or not present on EKG older than 6 months.
Ongoing cardiac dysrhythmias of NCI CTCAE ≥ Grade 2, atrial fibrillation Grade 2 or higher (resolution of atrial fibrillation to Grade ≤1 following nonurgent medical intervention may be allowed with prior sponsor approval).
Hypertension that cannot be controlled by medications (eg, sustained >150/90 mmHg) despite optimal medical therapy. Participants with SBP ≥150 and/or DBP ≥100 on 3 or more occasions are excluded until BP is controlled (eg, ≤150/90) for at least 2 weeks.
LVEF<50% as determined by ECHO.
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.
