Clinical Trials

IRB Study Number 23-420

Status Recruiting

Institute Taussig Cancer Institute

Description

Part 1 Primary Objective:

 To assess safety and tolerability at increasing dose levels of PF-07799933 as monotherapy in cohorts of participants with BRAF-altered solid tumors in order to determine the monotherapy MTD/RDE.

Part 1 Secondary Objectives:

 To characterize the single and/or multiple dose PK of PF-07799933 as monotherapy.

 To evaluate preliminary anti-tumor activity of PF-07799933 as monotherapy.

 To characterize the multiple dose PK of PF-07799933 in combination with binimetinib or cetuximab.

Part 2 Primary Objective:

 To assess safety and tolerability at increasing dose levels of PF-07799933 in combination with binimetinib in cohorts of participants with BRAF altered solid tumors, in order to determine the MTD/RDE of PF-07799933 for each combination with binimetinib.

Part 2 Secondary Objectives:

 To characterize the single and/or multiple dose PK of PF-07799933 in combination with binimetinib.

 To evaluate preliminary anti-tumor activity of PF-07799933 in combination with binimetinib.

Part 3 Primary Objective:

 To evaluate anti-tumor efficacy of PF-07799933 in participants with BRAF-altered solid tumors.

Part 3 Secondary Objectives:

 To confirm the safety and tolerability of PF-07799933.

 To further evaluate the single and multiple dose PK of PF-07799933.

 To assess additional measures of anti-tumor efficacy of PF-07799933.

 To evaluate the effect of repeated administration of PF-07799933 on single dose PK of midazolam.

Inclusion Criteria

Age and Sex:

1. Participants age ≥18 (or the minimum country-specific age of consent if >18) at the time of informed consent.

 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. Admission of adolescents to the study will be as appropriate according to institutional and regulatory approvals.

Type of Participant and Disease Characteristics:

1. 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 4), and other study procedures.

2. Histological or cytological diagnosis of advanced/metastatic solid tumor including primary brain tumor.

3. Genomic Alteration requirements:

Documented evidence of a qualifying BRAF founder alteration (V600 or non-V600 Class II/Class III BRAF alteration), in tumor tissue and/or blood (ie ctDNA) as previously determined during normal clinical care by PCR or NGS-based laboratory assay in a CLIA or similarly certified laboratory at any time prior to Day 1. A Participant Registration Form clearly documenting the presence of the required biomarker must be provided to the sponsor or designee during the Screening period for confirmation that biomarker testing meets eligibility (see Appendix 17 for documentation requirements and examples). Other alterations may be eligible with prior sponsor approval.

1. Tissue Requirement:

Prior to enrollment, confirmation of availability of sufficient archival tissue for submission to the central laboratory or provision of a newly collected tissue sample (see Section 8.7).

 Archival tissue must be of sufficient quantity and quality (see Section 8.7.1) and be obtained within the last 6 months and after completing the most recent treatment with a MAPK pathway inhibitor-based therapy (if previously given). 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 MAPK inhibitor treatment) should be submitted.

1. Prior treatment requirements:

Parts 1 and Part 2:

 Disease progressed during/following last prior treatment and no satisfactory alternative treatment options. Participants for whom the risk:benefit ratio of a specific alternative treatment option is unfavorable in the opinion of the investigator may be eligible if the reason is clearly documented by the investigator and approved by the sponsor.

Part 3:

 Cohorts 1 and 3 (BRAF V600 mutant melanoma): Prior BRAF V600 inhibitor therapy required (eg active against BRAF monomer/Class I mutations, examples include encorafenib, vemurafenib, dabrafenib; see Appendix 18), prior MEK inhibitor therapy required (examples include binimetinib, cobimetinib, trametinib; see Appendix 18), and immune checkpoint inhibitor therapy required (examples include ipilimumab, nivolumab, pembrolizumab; see Appendix 18).

 Cohort 2 (BRAF Class II/Class III-altered other solid tumor). Note: Adolescent participants should have cancers that are relapsed after or refractory to standard therapy with no curative options or for which no standard therapies with curative intent exist.

1. Participants entering the study Part 3 must have at least 1 measurable lesion as defined by RECIST version 1.1 (RANO for primary brain tumors), if the only measurable lesion was previous treated with local therapy [radiation, surgery], it must have progressed since such local therapy according to the appropriate imaging criteria.

 Participants with only non-measurable disease are allowed for Parts 1 and 2.

Informed Consent:

1. Capable of giving signed informed consent/assent 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 and assent 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.

Other Inclusion criteria:

1. ECOG PS 0 or 1. ECOG PS2, if related to the participant’s underlying cancer, may be allowed with prior sponsor approval.

2. Adequate bone marrow function, defined as:

a. ANC ≥1,250/mm3 or 1.25 x 109/L;

b. Platelets ≥75,000/mm3 or 75 x109/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.

1. Adequate renal function, defined as:

 Estimated creatinine clearance ≥60 mL/min (≥50 mL/min for Part 3 dose expansion) 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.

1. Adequate liver function, defined as:

a. Total bilirubin ≤1.5 x ULN (unless the participant has documented Gilbert’s syndrome); ≤2.5 x ULN for HCC;

b. AST and ALT ≤2.5 x ULN;

c. Alkaline phosphatase ≤2.5 x ULN (≤5 x ULN in case of bone involvement/metastasis).

1. Presence or absence of brain involvement (brain metastases/primary brain tumor). Participants with brain metastases/primary brain tumor must meet all the following conditions.

Part 1 and Part 2 (dose escalation):

 Initially during Part 1, participants with brain involvement must be asymptomatic in the brain for at least 14 days prior to the start of study treatment, defined as:

 be neurologically asymptomatic from brain metastases/primary brain tumor;

 not require initiation of or an increase in steroid dosing to control neurologic symptoms due to brain metastases/primary brain tumor (see Section 6.8.7);

 not require initiation of or an increase in anti-epileptic dosing to control seizure activity due to brain metastases/primary brain tumor. Exception: anti-epileptic therapy to prevent neurologic symptoms caused by a pre-existing condition and not related to brain involvement is allowed provided there are no concerning DDIs. Antiseizure medications must meet any eligibility criteria outlined for concomitant medications (see Section 6.8, Appendix 8 and 9 for allowed/prohibited concomitant medications, including anti-epileptic therapy);

 completed any planned local treatment (eg whole brain RT or surgery) for brain metastases 14 days (2 days for SRS) prior to enrollment and recovered from local treatment related toxicity(ies). AND

 All parenchymal brain lesions, if present, must be ≤4 cm in longest diameter at the time of study screening (imaging evidence required).

 During Part 1, when steady-state (eg, on C1D15 pre-dose) plasma concentrations of PF-07799933 are consistent with inhibition of BRAF Class II alterations (based on preclinical data) in at least one-half of participants at the same dose level, subsequent participants entering the study during the remainder of Part 1 and Part 2 may have untreated and/or symptomatic brain involvement (defined as: any of the above 14 days prior to the start of study treatment), and/or have a lesion(s) ≤4 cm. Participants with primary glioma may be have lesions >4 cm.

Part 3 (dose expansion):

 Participants in Part 3 may have untreated and/or symptomatic brain involvement as defined above. In all cohorts, metastatic lesions to CNS must be ≤4 cm in longest diameter at the time of study screening (imaging evidence required). Participants with primary gliomas may have lesions >4 cm and must meet all other inclusion criteria. Participants who are diagnosed with other CNS involvement during the screening period must also meet these criteria.

1. 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 and discussion with sponsor).

Exclusion Criteria

Medical Conditions:

1. Other active malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, Bowen’s disease, carcinoma in situ, prostate intraepithelial neoplasm and ≤6 Gleason grade prostate cancer. Participants with a history of other curatively treated cancers must be reviewed by the sponsor prior to entering the study.
2. Major surgery (defined as an inpatient procedure performed under general anesthesia) within 28 days prior to study entry (Day 1), within 14 days for minor surgical procedure or craniotomy procedure. If craniotomy performed, neurological sequelae must have fully resolved. Participants having an implantable port placed can enter the study 1 week after the port is placed, assuming no complications have occurred, and the port is functioning normally.
3. WBRT radiation therapy within 14 days prior to study entry (Day 1). Limited focal radiation therapy (including SRS or Gamma-Knife) requires 2 days before study entry and the absence of any radiation-induced complications. If SRS or WBRT performed, neurological sequelae must have fully resolved and steroid dosing must meet Inclusion Criteria.
4. Brain metastasis/primary brain tumor requiring immediate local intervention (surgery, radiosurgery) in the opinion of the investigator.
5. 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 they are stable, asymptomatic and on a stable dose of anticoagulant for a minimum of 4 weeks prior to starting study treatment (Day 1). Upper extremity catheter-related venous thrombosis is not considered a thromboembolic event for this trial and is not an exclusion.
6. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery, or inability to swallow and retain study treatment. Gastroesophageal reflux disease under treatment with H2 blockers or antacids is allowed provided dosing instructions in the protocol are followed. Use of PPIs are not allowed within 7 days of study start (C1D1) and during study treatment (see Section 6.8.1).
7. Concurrent neuromuscular disorder that is associated with elevated CK (eg, inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
8. 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.
9. 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:

1. Systemic anti-cancer therapy (approved or investigational) ongoing at the time of study entry (Day 1). (Refer to Inclusion criteria #6, #14, Exclusion criterion #12, and Section 8.2.1 documentation of previous anti-cancer therapy). Exceptions include:

 Hormone therapy, if consistent with inclusion/exclusion criteria, concomitant therapy and supportive care guidelines (see Section 6.8.3), may be allowed if approved by the sponsor.

1. Prior therapy exclusion:

Part 3:

 Participants who have undergone treatment with any RAF inhibitor active against BRAF dimers/Class II/III alterations (eg, PXL8394, BGB-3245, BGB-659, KIN-2787, LY3009120, TAK632; see Appendix 18).

1. Current use or anticipated need for any prohibited medication (refer to Section 6.8 Concomitant Therapy and Appendix 8).

Prior/Concurrent Clinical Study Experience:

1. Participation in other studies involving investigational drug(s) within 2 weeks or 5 half-lives (whichever is shorter) prior to study entry (Day 1). A participant may be eligible even if they are in the follow-up phase of an investigational study as long as they haven’t received treatment in the study for 4 weeks or 5 half-lives (whichever is shorter) prior to study entry (Day 1). Cases must be discussed with sponsor’s medical monitor to judge eligibility.

Diagnostic Assessments:

1. Serum or urine pregnancy test (for females of childbearing potential) positive at Screening or Day 1.
2. 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 circumstances 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. In the event of continued test positivity participant may be enrolled upon sponsor medical monitor approval.

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-c/hcp/diagnosis-testing/) for further details.

 HBV:

 This criterion excludes participants with a positive HBsAg (ie, either acute or chronic active hepatitis).

 However, participants with HBV antibody positivity indicating immunity, either due to vaccination or prior natural infection, are eligible.

 Participants with positive anti-HBcAb but negative HBsAg and anti-HBsAb profile may, depending on clinical circumstances, be eligible. 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 have yet turned positive. 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).

1. Impaired cardiovascular function or clinically significant cardiovascular disease or arterial thrombotic disease including, but not limited to, the following:

 Screening or Baseline standard 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, screening or baseline QTcF>470 ms, 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 ms, or QRS complex exceeds 120 ms, the ECG should be repeated 2 more times and the average of the 3 QTcF or QRS complex 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 over-read by a physician experienced in reading ECGs before excluding participants. Cases must be discussed in detail with the sponsor to judge eligibility. 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.

 Any of the following in the previous 6 months: myocardial infarction, long QT syndrome, Torsade de Pointes, any ventricular arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), any clinically important atrial arrhythmia, unstable angina, coronary/peripheral artery bypass graft, symptomatic CHF (New York Heart Association Class ≥II), cerebrovascular accident, transient ischemic attack, arterial thrombotic event requiring the use of thrombolytic agent, and/or other clinical significant episode of thrombo-embolic disease.

 New serious conduction system abnormalities (eg, left anterior hemiblock) which has occurred within the last 6 months, and/or not present on ECG older than 6 months.

 Ongoing cardiac dysrhythmias of NCI CTCAE ≥ Grade 2 (e.g requiring cardioversion, ablation procedure, pacemaker placement within the last 3 months. Stable dose(s) of anti-arrhythmic medications does not qualify as medical intervention. History of chronic atrial fibrillation present for ≥ 3 months, on stable medication regimen is permitted).

 Hypertension that cannot be controlled by medications (eg, >150/90 mmHg) despite optimal medical therapy. Participants with SBP ≥160 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 Exclusions:

1. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.