| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
HR+ HER2- Metastatic Breast Cancer, Ovarian Cancer, Small Cell Lung Cancer (Part 1 also had Triple Negative BC and Non Small Cell Lung Cancer)
|
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast Cancer, Ovarian Cancer, SCLC (Part 1 also had TNBC and NSCLC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10041067 |
| E.1.2 | Term | Small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1A:
Safety and tolerability PF-4091 in patients with HR+ HER2- advanced or mBC patients, recurrent/advanced or mTNBC or advanced platinum resistant epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer or advanced small cell and non small cell lung cancer to estimate the MTD and select the RDE for PF-4091 as a single agent.
Parts 1B and 1C:
Safety and tolerability of PF-4091 at the single agent RDE in combination with endocrine therapy (Fulvestrant or Letrozole) or endocrine therapy
and palbociclib in HR+ HER2- advanced or mBC in order to establish the RDE for PF-4091 in combination.
Part 2:
Evaluate antitumor activity and confirm the safety and tolerability of PF-4091 alone in advanced or metastatic SCLC, advanced platinum resistant epithelial ovarian cancer/fallopian tube/primary peritoneal cancer, TNBC and advanced or metastatic NSCLC or in combination with fulvestrant (doublet) in patients with HR+ HER2- advanced or mBC. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1A, 1B and 1C:
• To evaluate the single and multiple dose PK and document any preliminary evidence of anti-tumor activity of PF-07104091 when given as a single agent (Part 1A) and in combination with palbociclib and endocrine therapy (fulvestrant or letrozole) or with endocrine therapy alone (Part 1B and 1C).
Part 2:
• To further explore preliminary antitumor activity and further evaluate the PK of PF-07104091 as a single agent or in combination with fulvestrant at the MTD/RDE.
• To evaluate the effect of food on the PK of PF-07104091 as a single agent at/near MTD/RDE (Participants in Part 1 who are enrolled in the food effect on PF-07104091 PK substudy may be included in this analysis).
• To evaluate pharmacodynamic effects of PF-07104091 in tumor tissue following single-agent PF-07104091 treatment. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Females and/or male participants age ≥18 years.
2. Part 1:
• Participants with HR-positive HER2-negative advanced or metastatic breast cancer (third line plus setting) (histologically or cytologically proven).
• Participants with locally recurrent/advanced or metastatic TNBC who have received up to 3 prior lines of chemotherapy in the advanced or metastatic setting.
• Participants with advanced platinum resistant epithelial ovarian cancer (EOC)/fallopian tube cancer/primary peritoneal cancer (PPC) (histologically or cytologically proven) who have received at least 1 systemic anti-cancer therapy containing a platinum analog.
Part 1A only:
• Participants with cytological diagnosis of advanced/metastatic SCLC.
• Participants with or cytological diagnosis of advanced/metastatic NSCLC.
• Participants with HR-positive HER2-negative advanced or metastatic breast cancer (second line plus setting) (histologically or cytologically proven).
Part 2A:
• Participants with cytological diagnosis of advanced / metastatic SCLC
Part 2B:
• Participants with advanced platinum resistant epithelial ovarian cancer (EOC)/fallopian tube cancer/primary peritoneal cancer (PPC) (histologically or cytologically proven)
• Availability of adequate archival tumor tissue for submission to the sponsor/central laboratory for confirmatory testing of CCNE1 amplification and additional molecular analyses.
Part 2C:
• Participants with HR-postive HER2-negative advanced or metastatic breast cancer after prior ET-CDK4/6 inhibitor therapy (histologically or cytologically proven).
3. Participants entering the study in the expansion cohort have at least one measurable lesion as defined by RECIST version 1.1 that has not been previously irradiated).
4. ECOG PS 0 or 1.
5. Adequate Bone Marrow Function, including:
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.
6. Adequate Renal Function, including:
a. Estimated creatinine clearance ≥50 mL/min could be acceptable as calculated using the method standard for the institution. In equivocal cases, a 24-hour urine collection test can be used to estimate the creatinine clearance more accurately.
7. Adequate Liver Function, including:
a. Total serum bilirubin ≤1.5 x ULN unless the participant has documented Gilbert 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).
8. Resolved acute effects of any prior therapy to baseline severity or CTCAE Grade ≤1 except for AEs not constituting a safety risk by investigator judgment.
9. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
10. 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. |
|
| E.4 | Principal exclusion criteria |
1. Participants with known symptomatic brain metastases requiring steroids.
2. 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.
3. Major surgery within 3 weeks prior to study entry.
4. Radiation therapy within 3 weeks prior to study entry.
5. Systemic anti-cancer therapy within 4 weeks prior to study entry (6 weeks for mitomycin C or nitrosoureas) or 5 half-lives (whichever is shorter) of the agent(s) prior to receive the study intervention treatment is required.
6. Prior irradiation to >25% of the bone marrow.
7. Participants with active, uncontrolled bacterial, fungal, or viral infection, including HBV, HCV, and known HIV or AIDS related illness.
8. COVID-19/SARS-CoV-2: This protocol excludes participants with active infections, as noted above.
9. Baseline 12-lead ECG that demonstrates clinically relevant abnormalities that may affect participant safety or interpretation of study results.
10. Any of the following in the previous 6 months: myocardial infarction, long QT syndrome, Torsade de Pointes, arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), serious conduction system abnormalities, 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).
11. Anticoagulation with vitamin K antagonists or factor Xa inhibitors is not allowed. Anticoagulation with subcutaneous heparin is allowed.
12. Hypertension that cannot be controlled by medications (eg, >150/90 mmHg) despite optimal medical therapy.
13. Participation in other studies involving investigational drug(s) within 2 weeks prior to study entry.
14. Known or suspected hypersensitivity to active ingredient/excipients in PF-07104091.
15. Active inflammatory gastrointestinal disease, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery.
16. 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).
17. Participants with an indwelling catheter that has an external component such as those used for drainage of effusion(s) or central venous catheter that is externally exposed (eg, peripherally inserted central catheter (PICC) line).
18. Previous high dose chemotherapy requiring stem cell rescue.
19. Known abnormalities in coagulation such as bleeding diathesis, or treatment with anticoagulants precluding intramuscular injections of goserelin.
20. Known or suspected hypersensitivity to active ingredient/excipients of PF-07104091, palbociclib (or equivalent agent to induce chemical menopause).
21. Current use or anticipated need for food or drugs that are known strong CYP3A4/5 or UGT1A9 inhibitors, including their administration within 5 half-lives of the CYP3A4/5 or UGT1A9 inhibitor prior to first dose of investigational product.
22. Current use or anticipated need for drugs that are known strong CYP3A4/5 or UGT1A9 inducers, including their administration within 5 half-lives of the CYP3A4/5 or UGT1A9 inducer prior to the first dose of investigational product.
23. Current use or anticipated need for drugs that are known sensitive UGT1A1 substrates with narrow therapeutic index (eg SN-38 [active metabolite of irinotecan], irinotecan, belinostat).
24. Serum pregnancy test (for females of childbearing potential) positive at screening. Breastfeeding female patients (including patients who intend to interrupt breastfeeding).
25. 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.
26. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1A, Part 1B and Part 1C:
•First cycle DLTs.
•AEs as characterized by type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 5.0), timing, seriousness, and relationship to study therapy.
•Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE version 5.0), and timing.
•Vital sign abnormalities.
•Heart rate corrected QT interval (eg, QTcF).
Part 2
•Preliminary antitumor activity measure for efficacy includes ORR, as assessed using RECIST 1.1.
•Safety and tolerability:
•Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), timing, seriousness, and relationship to study therapy.
•Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v 5.0), timing, seriousness, and relationship to study therapy.
•Vital sign abnormalities.
•Heart rate corrected QT interval (eg, QTcF). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Number of patients with dose limiting toxicities in the Dose Escalation portion [ Time Frame: up to 28 days ]
•Safety and Tolerability as assessed by adverse event and safety monitoring for patients enrolled in the Dose Escalation, Dose Finding and Dose Expansion Arms [ Time Frame: Weekly during Cycle 1 (each cycle is 28 days) and 2 and then every 28 days through study completion, up to approximately 24 months ]
•Objective Response Rate (ORR) observed in patients in the Dose Expansion Arms [ Time Frame: baseline up to approximately 24 months ] Number of patients in each Arm. ORR (number of patients with a Partial Response (PR) + Complete Response (CR) relative to the number of evaluable patients |
|
| E.5.2 | Secondary end point(s) |
PK parameters of PF-07104091:
•Single Dose Cmax, Tmax, AUClast, and as data permit, AUCinf, CL/F, Vz/F, and t1/2.
•Multiple Dose (assuming steady state is achieved) Cmax,ss, Tmax,ss, AUC,ss, Cmin,ss, CL/F,ss, and as data permit, V/F, ss, t1/2, and Rac (AUC,ss/AUC,sd).
•ORR, as assessed using RECIST version 1.1.
•Time to event endpoints: eg, DoR, PFS, TTP, CBR.
•Time to event endpoints: eg, DoR, PFS, CBR, overall survival OS and TTP.
•PK parameters of PF-07104091.
•Single dose: Cmax, Tmax and AUClast.
•Multiple dose (assuming steady state is achieved): Cmax,ss, Tmax,ss, AUClast, Cmin,ss, and Rac.
•PK parameters of PF-07104091 given with and without food.
•Changes in cell cycle biomarkers (eg, phosphor Rb, Ki 67) in paired pre- and on treatment tumor biopsies. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Single and Multiple Dose: PK endpoints in Part 1 and Part 2 [ Cycle 1 and Day 1 of each subsequent cycle and at study completion visit, up to 24 months ]
•Tumor Response observed in patients [up to approximately 24 months ]
•Duration of Response (DOR) in patients enrolled in the Part 1 and Part [ up to 24 months ]
•Progression Free Survival (PFS) observed in patients in Part 1 and Part [ up to 24 months ]
•Time to Progression (TTP) observed in patients enrolled in Part 1 and Part [ up to 24 months ]
•Overall Survival observed in patients enrolled in Part 2 [up to 24 months ]
•Pharmacodynamic (PD) biomarkers in tumor tissue in patients enrolled in Part 1 and Part [ Screening, Cycle 1, Cycle 2 and 3 and at the study completion visit, up to 24 months] |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability, biomarker assessment |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| China |
| Japan |
| United States |
| Bulgaria |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study is defined as the date of the last visit of the last participant in the study. The maximum duration of the trial will be approximately 2 years after last participant first dose. The study may also be terminated at any time at the discretion of the Sponsor. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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