| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Locally recurrent (not amenable for curative intent) or metastatic squamous cell carcinoma of the of the oral cavity, oropharynx, hypopharynx, or larynx;
metastatic castration-resistant prostate cancer without small cell features |
|
| E.1.1.1 | Medical condition in easily understood language |
Locally recurrent or metastatic squamous cell carcinoma of the head and neck;
metastatic castration-resistant prostate cancer without small cell features |
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| 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 | 10076506 |
| E.1.2 | Term | Castration-resistant prostate 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 | 10063569 |
| E.1.2 | Term | Metastatic squamous cell carcinoma |
| 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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| 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 |
Phase 1b:
•To assess the dose-limiting toxicity (DLT) rate of avelumab in combination with bempegaldesleukin (NKTR-214) (Combination A) and talazoparib (Combination B) or enzalutamide (Combination C) in order to determine the recommended Phase 2 dose (RP2D) for the combinations.
Phase 2:
•Combination A: To assess ORR of avelumab in combination with bempegaldesleukin (NKTR-214) in participants with locally recurrent or metastatic SCCHN
•Combination B: To assess soft tissue ORR of avelumab in combination with bempegaldesleukin (NKTR-214) and talazoparib in participants with DDR defect positive mCRPC.
•Combination C: To assess the PSA response rate of avelumab in combination with bempegaldesleukin (NKTR-214) and enzalutamide in participants with mCRPC after progression on abiraterone.
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|
| E.2.2 | Secondary objectives of the trial |
1. To assess the overall safety and tolerability of the combinations (A, B and C).
2. To assess other measures of anti tumor activity
3. To characterize the PK of avelumab, bempegaldesleukin (NKTR-214), and talazoparib or enzalutamide when given in combination.
4. To assess the immunogenicity of avelumab and bempegaldesleukin (NKTR-214) when combined together and with talazoparib or enzalutamide.
5. To assess the correlation of anti-tumor activity with PD-L1 expression level in baseline tumor tissue.
6. Combination A: To assess the correlation of anti-tumor activity with PD-L1 expression level in on-treatment tumor tissue. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
SCCHN and mCRPC
- >/= 18 years of age and give consent
- Must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures as specified in the protocol
- Contraceptive use must meet requirements outlined in the protocol and should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- COG of 0 or 1
- Participants must have adequate bone marrow function without hematopoietic growth factor or transfusion support within 14 days prior to and including C1D1 per protocol
- Participants must have adequate liver function by C1D1 per protocol
- Participants must have adequate renal function by C1D1 per protocol
- All participants must provide tumor tissue as described in protocol
Combination A- SCCHN
- Histological diagnosis of locally recurrent (not amenable for curative intent) or metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx and both of the following:
oNo prior systemic treatment for unresectable locally recurrent or metastatic disease
Exception: If prior systemic chemotherapy treatment was given as part of chemoradiotherapy treatment, disease-free interval after the last administration of systemic chemotherapy treatment must be at least 6 months
o Measurable disease by RECIST v1.1 with at least 1 measurable lesion
Combination B & C- mCRPC
- mCRPC without small cell features meeting the following criteria:
- Castration as defined by both of the following:
o Serum testosterone ≤1.73 nmol/L (50 ng/dL) at the time of enrollment (prior to treatment with study drug on C1D1)
o Bilateral orchiectomy or ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) agonist/antagonist (surgical or medical castration)
- Progressive disease at the time of enrollment (prior to treatment with study drug on C1D1) defined as 1 or more of the following 3 criteria:
o A minimum of 3 consecutive rising PSA values with an interval of at least 1 week between determinations. The screening PSA value must be ≥2 µg/L (2 ng/mL) if qualifying solely by PSA progression
o Radiographic soft tissue disease progression as defined by RECIST v1.1 for soft tissue
o Radiographic bone disease progression defined by Prostate Cancer Working Group 3 (PCWG3) with 2 or more new metastatic lesions on bone scan (confirm ambiguous results by other imaging modalities)
Combination B only (mCRPC)
- Progressed on at least 1 line of second generation anti-androgen therapy (e.g. enzalutamide and/or abiraterone acetate/prednisone) for treatment of mCRPC
- Have received at least 1, but no more than 1, prior taxane-based chemotherapy regimens for mCRPC or were deemed unsuitable, declined, or did not have access to these therapies
o Participants may have received radium -223, which does not count for a line of prior chemotherapy regimen
- Measurable disease by RECIST v1.1 with at least 1 measurable lesion
Phase 2 Only:
- Required to have their disease assessed for a genomic defect in one or more pre-defined DDR genes based on testing de novo or archival tumor tissue using the Foundation One® Test
Combination C only (mCRPC)
- Participants with non-measurable disease (including disease affecting bone only) as determined by RECIST v1.1 are allowed
- Participants must have progressed on 1 line of abiraterone acetate/prednisone anti-androgen therapy for treatment of mCRPC
- Participants must have not had any prior chemotherapy for the treatment of mCRPC
o Prior treatment with radium 223 is allowed and it does not count as a prior chemotherapy regimen
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|
| E.4 | Principal exclusion criteria |
SCCHN and mCRPC
- Known prior severe hypersensitivity to investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCT CTCAE v4.03 Grade ≥3)
- Known history of: immune-mediated colitis, inflammatory bowel disease, pneumonitis, or pulmonary fibrosis
- Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible
- Prior organ transplantation
- Vaccination within 4 weeks prior to C1D1 and while on trial is prohibited except for administration of inactivated vaccines
- Known symptomatic brain lesions requiring steroids
o Exception: participants with previously diagnosed brain lesions are eligible if they meet all of the following criteria:
have newly diagnosed small brain lesions which do not require treatment
have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to C1D1
have discontinued corticosteroid treatment for these lesions for at least 4 weeks prior to C1D1; and are neurologically stable
Known history of testing positive for HIV or known AIDS
- Positive HBV surface antigen, or positive HCV RNA if anti-HCV antibody screening tests positive
- Active infection requiring systemic therapy within 14 days prior to C1D1.
- Other acute or chronic medical or psychiatric conditions
- Clinically significant (i.e., active) cardiovascular disease including the following:
o Documented left ventricular ejection fraction < 45%
o Cerebral vascular accident/stroke, Myocardial infarction (<6 months prior to C1D1)
o Unstable angina
o Congestive heart failure
o Serious cardiac arrhythmia requiring medication
- Diagnosis of any other malignancy within 2 years prior to C1D1, except for adequately treated basal cell or quamous cell skin cancer, carcinoma in situ of the breast, bladder or of the cervix
- Prior immunotherapy with IL-2 agents or anti PD-1, anti PD-L1, anti PD-L2, or anti- CTLA-4 antibody. Prior treatment with Sipuleucel-T for participants with mCRPC is allowed
- Current use of immunosuppressive medication at the time of C1D1, EXCEPT for the following permitted steroids:
o Intranasal, inhaled, topical steroids, eye drops or local steroid injection; systemic corticosteroids at physiologic doses ≤10 mg/day of prednisone; steroids as premedication for hypersensitivity reactions
- Bisphosphonate or denosumab dosage that was not stable for at least 2 weeks before C1D1 for participants receiving these therapies
- Prior radiation therapy within 14 days prior to C1D1. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided it has been completed 14 days prior to C1D1 and no clinically significant toxicities are expected
- Major surgery within 4 weeks prior to C1D1
- Participation in other studies involving investigational drug(s) within 2 weeks prior to C1D1
- Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, alopecia and sensory neuropathy Grade ≤2, or other Grade ≤2 AEs not constituting a safety risk, based on Investigator's judgment (I’s), are acceptable
- I site staff members or participants who are Pfizer employees, directly involved in the conduct of the study and their family, site staff members otherwise supervised by the I
Combination A
- Participants will be excluded if they have a history of prostate cancer except in the cases below:
- Low-Grade prostate cancer on surveillance with no plans for treatment intervention, provided that the following criteria are met:
o Stage T2N0M0 or lower
o PSA below lower limit of normal by local laboratory is allowed
o Prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms is also allowed
Combination B
- Prior treatment with a PARP inhibitor
o Current (within 7 days prior to C1D1) or anticipated use of medications: including strong P-gp inhibitors, strong P-gp inducers, strong inhibitors of breast cancer resistance protein
-Conditions that may impair intake or absorption of talazoparib as follows: inability to swallow capsules or tablets; known malabsorption syndrome; or baseline diarrhea ≤ Grade 1
Combination C
- Prior treatment with second generation androgen receptor antagonist other than abiraterone/prednisone
- Current (within 7 days prior to C1D1) or anticipated use of medications (strong/moderate inducers for CYP3A4, strong CYP2C8 inducers and CYP2C8 inhibitors, and substrates of CYP3A4, CYP2C9, and CYP2C19)
- Conditions that may impair intake or absorption of enzalutamide as follows: inability to swallow capsules or tablets; known malabsorption syndrome; or baseline diarrhea ≤ Grade 1
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b:
•DLT during the DLT evaluation period (Cycle 1)
Phase 2:
•Combination A: Confirmed objective response (OR) as determined by the investigator using RECIST v1.1 (Appendix 9).
•Combination B: Confirmed soft tissue OR as determined by the investigator using RECIST v 1.1 (Appendix 9) with no evidence of confirmed bone disease progression on repeat bone scan at least 6 weeks later per prostate cancer working group 3 (PCWG3) criteria (Appendix 10).
•Combination C: Confirmed prostate specific antigen (PSA) response decrease ≥ 50% from baseline confirmed by a second consecutive assessment at least 3 weeks later.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Individual timepoints are included in each bullet point above |
|
| E.5.2 | Secondary end point(s) |
1. a) Adverse events (AEs) as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v4.03), timing, seriousness, and relationship to study therapy.
b)Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v4.03) and timing.
2. a)Time-to-event endpoints as determined by the investigator, using RECIST v1.1 (Combination A) and in participants with mCRPC (Combinations B and C), RECIST v1.1 (soft tissue disease) and PCWG3 (bone disease), including time to tumor response (TTR), duration of response (DR), progression free survival (PFS), and Overall Survival (OS).
b)Combination B: Confirmed PSA response 50% decrease from baseline confirmed by a second consecutive assessment at least 3 weeks later.
c)Combination C: Confirmed soft tissue OR as determined by the investigator using RECIST v 1.1 (Appendix 9) with no evidence of confirmed bone disease progression on repeat bone scan at least 6 weeks later per PCWG3 criteria (Appendix 10).
d)Combination C: Circulating tumor cells CTC count conversion (decrease in CTC count from ≥ 5 CTC per 7.5 mL of blood at baseline to < 5 CTC per 7.5 mL of blood at any assessment on treatment), and CTC0 (CTC0 is defined as a CTC count of ≥1 CTC per 7.5 mL of blood at baseline and 0 CTC per 7.5 mL of blood at any assessment on treatment).
e)Combinations B and C: Time to PSA progression (TTPSAP) defined according to the consensus guidelines of the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria.
3. PK parameters including trough concentrations (Ctrough) for avelumab, bempegaldesleukin (NKTR-214), talazoparib, enzalutamide and N-desmethyl-enzalutamide and maximum concentrations (Cmax) for avelumab and bempegaldesleukin (NKTR-214).
4. Anti-drug antibody (ADA) and neutralizing antibodies (NAb) against avelumab, bempegaldesleukin (NKTR-214) and IL-2 when combined together and with talazoparib or enzalutamide
5. PD L1 expression level in baseline tumor tissue
6.Combination A: PD-L1 expression level in on-treatment tumor tissue |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Individual timepoints are included in each bullet point above |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| 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 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| dose-range finding toxicity |
|
| 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 | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Belgium |
| Canada |
| Italy |
| Poland |
| Spain |
| United States |
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| 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
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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