A Phase 1/2a study of PF-07220060 in Participants with Advanced Solid Tumors

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 Aug 2022 → ongoing

Decision date (initial)

2024-06-19

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer Inc.

External identifiers

EU CT number

2024-512120-11-00

EudraCT number

2020-002938-33

ClinicalTrials.gov

NCT04557449

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Pharmacokinetic, Safety

Part 1A:
- To assess the safety and tolerability of increasing doses of PF-07220060 as a single agent in successive cohorts of participants with HR-positive
advanced HER2-negative or HR-positive HER-2 positive advanced or mBC, adenocarcinoma of NSCLC, prostate cancer, CRC, liposarcoma and tumor types with CDK4 or CCND1 amplification
in order to estimate the MTD and select the RP2D and/or RDE.

Part 1B and Part 1C:
- To assess the safety and tolerability of PF-07220060 in combination with letrozole or fulvestrant in participants with HR-positive HER2-negative advanced or mBC (2L+ setting), in order to estimate the MTD and select the RP2D and/or RDE of PF-07220060 in combination with letrozole or fulvestrant.

Part 1D:
- To evaluate the effect of food on the PK of PF-07220060 administered at the proposed monotherapy RP2D and/or RDE.
- To assess the safety and tolerability of PF-07220060 as a single agent in participants with HR-positive advanced HER2-negative or HR positive HER2-positive advanced or mBC,
adenocarcinoma of NSCLC, prostate cancer, CRC, liposarcoma and tumor types with CDK4 or CCND1 amplification at the monotherapy RP2D and/or RDE.

Part 1E:
- To evaluate the effect of repeated administration of PF-07220060 at the RP2D and/or RDE on single dose PK of oral midazolam.
- To assess the safety and tolerability of PF-07220060 as a single agent in participants with HR-positive advanced HER2-negative or HR positive HER2-positive advanced or mBC, adenocarcinoma of NSCLC, prostate cancer, CRC, liposarcoma and tumor types with CDK4 or CCND1 amplification at the monotherapy RP2D and/or RDE.

Part 1F:
- To assess the safety and tolerability of PF-07220060 in combination with enzalutamide in participants with mCRPC in order to estimate the MTD and select the RP2D and/or RDE of the
combination.

Parts 2A, 2B, 2C, and 2D:
• To further assess the safety and tolerability of PF- 07220060 in combination with:
• Parts 2A, 2B, and 2C: letrozole or fulvestrant at the selected RP2D and/or RDE in
participants with HR-positive HER2-negative advanced or mBC.
• Part 2D: enzalutamide at or below the selected RP2D and/or RDE in participants with mCRPC.

Part 2E:
• To further assess the safety and tolerability of PF- 07220060 in monotherapy vs in combination with fulvestrant at the selected RP2D and/or RDE in participants with HR-positive HER2-negative advanced or mBC.

Secondary objectives 7

1. To evaluate the single- and multiple-dose PK of PF-07220060 when given as a single agent (Part 1A), or in combination with letrozole or fulvestrant (Part 1B and Part 1C, respectively) or in combination with enzalutamide (Part 1F).
2. To evaluate the multiple-dose PK of PF-07220060 when given with midazolam (Part 1E).
3. To evaluate PK of enzalutamide and its metabolite N-desmethyl enzalutamide when given in combination with PF-07220060 (Part 1F).
4. To assess preliminary evidence of antitumor activity of PF-07220060 as single agent or in combination with fulvestrant, letrozole, or enzalutamide.
5. Parts 2A, 2B, and 2C: • To estimate the anti-tumor activity of PF- 07220060 in combination with letrozole and fulvestrant at the estimated RP2D and/or RDE in participants with HR-positive HER2-negative advanced mBC. • To further evaluate PK of PF-07220060 in combination with letrozole or fulvestrant.
6. Part 2D: • To assess anti‑tumor activity of PF-07220060 in combination with enzalutamide in participants with mCRPC. • To assess the effect of PF-07220060 in combination with enzalutamide on participant reported outcomes. • To further evaluate the PK of PF-07220060 and of enzalutamide and its metabolite N-desmethyl enzalutamide in participants with mCRPC treated with the combination.
7. Part 2E: • To assess the anti-tumor activity of PF-07220060 in monotherapy vs in combination with fulvestrant at the estimated RP2D and/or RDE in participants with HR-positive HER2-negative advanced mBC. • To further evaluate PK of PF-07220060 in monotherapy vs in combination with fulvestrant.

Conditions and MedDRA coding

Part 2A, 2B, 2C & 2E HR-positive /HER2-negative breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Disease requirements for Part 1 a. Part 1B and Part 1C: - Refractory HR-positive/HER2-negative (2L+ with prior CDK4/6) breast cancer. b. Part 1A, Part 1D and Part 1E will include the above and:  Refractory HR-positive/HER2-positive breast cancer.  Tumors other than BC: NSCLC, prostate, CRC, liposarcoma, or tumors with previously confirmed CDK4 or CCND1 amplification according to local standard tests c. Part 1F: - Histological or cytological diagnosis of prostate cancer that has progressed from last therapy as per PCWG3.
2. 2. Disease requirements for Part 2 Part 2A, 2B, 2C and Part 2E: a. HR-positive/HER2-negative breast cancer Part 2D:  Histological or cytological diagnosis of castration resistant prostate cancer that has progressed from last therapy as per PCWG3.
3. 3. Lesion requirements a. For Part 1: participant must have evaluable lesion (including skin or bone lesion only). b. For Part 2A, 2B, 2C and Part 2E: participants must have measurable disease as defined per RECIST version 1.1. Tumor lesions previously irradiated or subjected to locoregional therapy will only be deemed measurable if progression at the treated site after completion of therapy is clearly documented. c. For Part 2D: Participants with evaluable disease by PCWG3. Participants with bone metastases only are allowed. Participants with biochemical recurrence only are excluded.
4. 4. Prior Systemic Treatment: a. For Part 1: •HR-positive/HER2-negative Breast Cancer (Part 1A/Part 1B/Part 1C/ Part 1D/Part 1E): •Participants should have received: •at least 1 line of SOC, including CDK4/6 inhibitor therapy for advanced or metastatic disease, or if CDK4/6 inhibitors are available but not considered appropriate in the opinion of the investigator, participants may be enrolled if a compelling clinical rationale is provided by the investigator and approved by the sponsor. or •at least 1 line of anti-endocrine therapy in countries without CDK4/6 inhibitor approval or reimbursement, for advanced or metastatic disease. •Participants in Part 1C who received fulvestrant as part of the last prior therapy are eligible. See Section 6.1.1.3. Prior chemotherapies for advanced disease setting are allowed in both cases. •HR-positive/HER2-positive Breast Cancer (Part 1A/Part 1D/Part 1E): Participants should have received at least one prior treatment of approved HER2 targeting therapy. •Tumors Other Than Breast Cancer (Part 1A/Part 1D/Part 1E): tumor that is resistant to at least 2 lines of standard systemic therapy for advanced or recurrent disease or for which no standard therapy is available. For Part 1F: tumor that is resistant to at least 1 line of standard systemic therapy for advanced or recurrent disease or for which no standard therapy is available. Note: Maintenance with LHRH agonist or antagonist is permitted. b. For Part 2: Part 2A and 2E: •Participants must have received at least 1 line of SOC, including prior CDK4/6 inhibitor, for advanced/metastatic breast cancer. •Prior chemotherapies for advanced disease setting are allowed. •Prior fulvestrant, mTOR and/or PI3K inhibitors are allowed. Part 2B: •Participants who have not received any prior systemic anti-cancer therapies for advanced/metastatic breast cancer. Part 2C: •Progressed during treatment or within 12 months of completion of adjuvant therapy with an aromatase inhibitor if postmenopausal, or tamoxifen if pre-or perimenopausal, or •Progressed while on or within 1 month after the end of prior aromatase inhibitor therapy for advanced/metastatic breast cancer if postmenopausal, or prior endocrine treatment for advanced/metastatic breast cancer if pre- or perimenopausal. •One previous line of chemotherapy for advanced/metastatic disease is allowed in addition to endocrine therapy. Part 2D: •Received prior treatment with abiraterone in any setting. Note: Maintenance of LHRH agonist or antagonist is required unless treated with bilateral orchiectomy. •Enzalutamide, apalutamide-, darolutamide- and CDK4/6- inhibitor naïve. •Up to 1 prior line of chemotherapy in any setting.
5. General Inclusion Criteria 1. Participants in both Part 1 and Part 2 (except for Part 2B and Part 2D) must be refractory to or intolerant of existing therapies known to provide clinical benefit for their condition.
6. Participants age ≥18 years (all parts).
7. ECOG PS of 0 or 1.
8. Adequate bone marrow function, as evidenced by: 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. Limited transfusions to reach this value are allowed, after discussion with sponsor’s medical monitor. There should not be a chronic need for transfusions in the recent past (approximately 3 months).
9. Adequate renal function, defined as: a. estimated creatinine clearance ≥50 mL/min as calculated using the method standard for the institution. In equivocal cases, a 24-hour urine collection test may be used to estimate the creatinine clearance more accurately.
10. Adequate liver function, as evidenced by: a. Total serum bilirubin ≤1.5 × ULN unless the participant has documented Gilbert syndrome (in which case, up to total serum bilirubin ≤3.0 × ULN will be allowed); b. AST and ALT ≤2.5 × ULN; ≤5.0 × ULN if there is liver involvement by the tumor; c. ALKP ≤2.5 × ULN (≤5.0 × ULN in case of bone or liver metastasis).
11. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1 except for AEs not constituting a safety risk as determined by the investigator.
12. Is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures
13. 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.
14. Women of any menopausal status are allowed; however, women who are not considered post-menopausal are allowed to enroll if amenable to be treated with the LHRH agonist goserelin. Patients must have commenced treatment with goserelin or an alternative LHRH agonist at least 4 weeks prior to enrollment. If patients have received an alternative LHRH agonist prior to study entry, it is preferable to switch to goserelin for the duration of the trial. However other LHRH antagonists, such as leuprolide is acceptable.

Exclusion criteria 26

1. For Part 1D only: Participants who have had a gastrectomy or have dietary or other restrictions that preclude a 10 hour overnight fast (water permitted) or consumption of the high fat, high calorie meal.
2. For Part 2B,  Prior neoadjuvant or adjuvant treatment with a non-steroidal aromatase inhibitor (ie, anastrozole or letrozole) with disease recurrence while on or within 12 months of completing treatment.  Prior treatment with any CDK4/6 inhibitor.
3. For Part 2C only: prior treatment with any CDK inhibitor, or fulvestrant, or everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway.
4. Known active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Participants with a history of CNS metastases or cord compression are eligible if they have been definitively treated (eg, radiotherapy, stereotactic surgery) and are clinically stable off anticonvulsants and steroids for at least 4 weeks before enrollment and have no evidence of progression at time of study enrollment.
5. Participants with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term (including participants with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement).
6. 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. Other indolent cancers with expectations of long-term survival that do not interfere with radiographic assessment of the primary cancer under study may be allowed with prior sponsor approval.
7. Major surgery within 4 weeks prior to study entry.
8. RT with treatment intent within 4 weeks prior to study entry. Any palliative RT must be completed within the 7 days prior to Day 1 of study intervention administration.
9. Last anticancer treatment within 2 weeks (or 5 half-lives, whichever is shorter), unless the last immediate anticancer treatment contained an antibody based agent(s) (approved or investigational), then the interval of 4 weeks (or 5 half-lives whichever is shorter) is required prior to receiving the study intervention. Part 1F: for participants whose last prior therapy was enzalutamide or apalutamide, the wash-out period should be at least 24 days. Part 1F and Part 2D: Last anti-hormonal therapy within 2 weeks prior to Cycle 1 Day 1, with the exception of LHRH agonist or antagonist as required in participants with mCRPC unless treated with bilateral orchiectomy.
10. Participation in other studies involving investigational product(s) within 4 weeks (or 5 half-lives, whichever is shorter) prior to study entry.
11. Previous high-dose chemotherapy requiring stem cell rescue.
12. Active and clinically significant bacterial, fungal, or viral infection, including but not limited to HBV, HCV, known HIV or AIDS- related illness. In equivocal cases, with positive serology, those participants with a negative viral load are potentially eligible provided the other entry criteria are met (refer to Table 1).
13. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results (eg, baseline QTc interval >470 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). If the baseline uncorrected QT interval is >470 msec, this interval should be rate-corrected using the Fridericia method and the resulting QTcF should be used for decision making and reporting. If QTc exceeds 470 msec, or QRS exceeds 120 msec, the ECG should be repeated 2 more times and the average of the 3 QTc or QRS values should be used to determine the participant’s eligibility. Computer-interpreted ECGs should be overread by a physician experienced in reading ECGs before excluding participants. Cases must be discussed in detail with sponsor’s medical monitor to judge eligibility.
14. Any of the following in the previous 6 months: myocardial infarction, congenital long QT syndrome, Torsades de pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), serious conduction system abnormalities (eg, bifascicular block (defined as right bundle branch and let anterior or posterior hemiblock), 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, or symptomatic pulmonary embolism; deep venous thrombosis; arterial occlusive disease; ongoing cardiac dysrhythmias of NCI CTCAE Grade ≥2, atrial fibrillation of any grade that is uncontrolled, or QTcF interval >470 msec at screening.
15. Blood pressure (≥150/90 mmHg despite optimal medical therapy) that cannot be controlled.
16. Therapeutic dose of anti-coagulant treatment is prohibited (prophylactic doses of anticoagulant are allowed).
17. Known abnormalities in coagulation such as bleeding diathesis.
18. Known or suspected hypersensitivity to active ingredient/excipients of PF-07220060, letrozole, fulvestrant, enzalutamide and/or goserelin (or equivalent agent to induce chemical menopause/chemical castration).
19. Active inflammatory GI disease, known diverticular disease or previous gastric resection or lap band surgery. Impairment of GI function or GI disease that may significantly alter the absorption of PF-07220060, such as history of GI surgery which may result in intestinal blind loops and clinically significant gastroparesis, short bowel syndrome, unresolved nausea, vomiting, active inflammatory bowel disease or diarrhea of CTCAE Grade >1.
20. Current use of drugs which have a risk for QTc prolongation (Refer to 10.8).
21. Current use or anticipated need for food or drugs that are known strong CYP3A4/5 or strong UGT2B7 inhibitors, including their administration within 5 half-lives of the CYP3A4/5 or UGT2B7 inhibitor, prior to first dose of investigational product. Current or anticipated use of moderate CYP3A4/5 or moderate UGT2B7 inhibitors (including their administration within 5 half-lives of the CYP3A4/5 or UGT2B7 inhibitor, prior to first dose of study intervention) should be avoided if possible, and any use will need to be reviewed and approved by the sponsor.
22. Current use or anticipated need for drugs that are known strong CYP3A4/5 or UGT2B7 inducers (except for enzalutamide as administered in this study), including their administration within 10 days or 5 half-lives of the CYP3A4/5 or UGT2B7 inducer, whichever is longer, prior to the first dose of study intervention.
23. Current use or anticipated need for PPI within 7 days prior to first dose of study intervention.
24. 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.
25. 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.
26. WOCBP who are currently pregnant or breast-feeding.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Part 1A, Part 1B, Part 1C, and Part 1F: •DLTs observed during the DLT evaluation period. • AEs as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study treatment. • Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing. •Incidence of clinically significant abnormal vital signs and ECG parameters.
2. 1D: • PK parameters (Cmax, Tmax, AUClast, and as data permit, AUCinf, CL/F, Vz/F, and t1/2) of PF- 07220060 given with and without food. •AEs as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study treatment. •Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing. •Incidence of clinically significant abnormal vital signs and ECG parameters.
3. 1D: •PK parameters (Cmax, Tmax, AUClast, and as data permit, AUCinf, CL/F, Vz/F, and t1/2) of PF- 07220060 given with and without food. •AEs as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study treatment. •Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing. •Incidence of clinically significant abnormal vital signs and ECG parameters.
4. Part 1E: • PK parameters of CYP3A4 probe substrate midazolam with and without PF-07220060: Cmax, Tmax, AUClast, and as data permit, t½, AUCinf, CL/F and Vz/F. • AEs as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study treatment.
5. Part 1E: • Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing. • Incidence of clinically significant abnormal vital signs and ECG parameters.
6. AEs as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), timing, seriousness, and relationship to study treatment. • Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0, and timing.

Secondary endpoints 5

1. Part 1A-1C and Part 1F (PF-07220060 PK)  Single dose: Cmax, Tmax, AUClast, and as data permit, AUCinf, CL/F, Vz/F, and t½.
2. Part 1A-1C, Part 1E, and Part 1F (PF 07220060 PK) • Multiple dose (assuming steady state is achieved): Css,max Tss,max, AUCt,ss, Css,min, and as data permit, CLss/F, Vss/F, t½. and Rac (AUCt,ss/AUCt).
3. Part 1F (Enzalutamide + N-desmethyl enzalutamide PK)  Peak and trough concentrations of enzalutamide and N-desmethyl enzalutamide.  ORR and CBR as assessed using RECIST version 1.1 (Parts 1A-1E) or PCWG3 (Part 1F).  PSA50 rate (Part 1F).  Time-to-event endpoints: DOR and PFS (Parts 1A-1F).
4. Parts 2A, 2B, 2C, and 2E:  ORR and CBR as assessed using RECIST version 1.1. Time-to-event endpoints: DOR and PFS.  Peak and trough concentrations of PF-07220060.
5. Part 2D:  ORR, DOR by PCWG3, PSA50 rate, rPFS, Time to first skeletal related events.  Symptoms and Health-Related Quality of Life as assessed by the FACT-P.  Peak and trough concentrations of PF-07220060, enzalutamide and N-desmethyl enzalutamide.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Third parties 2

Locations

2 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 22 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications